U.S. patent application number 12/747011 was filed with the patent office on 2010-11-25 for gamma secretase modulators.
Invention is credited to Robert G. Aslanian, Xianhai Huang, Anandan Palani.
Application Number | 20100297128 12/747011 |
Document ID | / |
Family ID | 40350182 |
Filed Date | 2010-11-25 |
United States Patent
Application |
20100297128 |
Kind Code |
A1 |
Huang; Xianhai ; et
al. |
November 25, 2010 |
GAMMA SECRETASE MODULATORS
Abstract
This invention provides novel compounds that are modulators of
gamma secretase. The compounds have the formula [Chemical formula
should be inserted here as it appears on abstract in electronic
form.] Also disclosed are methods of modulating gamma secretase
activity and methods of treating Alzheimer's disease using the
compounds of formula (I). ##STR00001##
Inventors: |
Huang; Xianhai; (Warren,
NJ) ; Palani; Anandan; (Bridgewater, NJ) ;
Aslanian; Robert G.; (Rockaway, NJ) |
Correspondence
Address: |
MERCK;PATENT DEPARTMENT (K-6-1, 1990)
2000 GALLOPING HILL ROAD
KENILWORTH
NJ
07033-0530
US
|
Family ID: |
40350182 |
Appl. No.: |
12/747011 |
Filed: |
December 9, 2008 |
PCT Filed: |
December 9, 2008 |
PCT NO: |
PCT/US08/86058 |
371 Date: |
July 29, 2010 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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61012857 |
Dec 11, 2007 |
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Current U.S.
Class: |
424/137.1 ;
514/248; 514/263.2; 514/265.1; 514/300; 514/303; 544/236; 544/276;
544/280; 546/113; 546/118 |
Current CPC
Class: |
A61P 27/16 20180101;
C07D 487/04 20130101; A61P 25/00 20180101; A61P 21/00 20180101;
A61P 25/28 20180101; C07D 471/04 20130101; A61P 29/00 20180101;
A61P 27/02 20180101; A61P 43/00 20180101; A61P 27/06 20180101; A61P
31/18 20180101; A61P 9/00 20180101; A61P 25/16 20180101 |
Class at
Publication: |
424/137.1 ;
544/236; 546/118; 546/113; 544/276; 544/280; 514/248; 514/303;
514/300; 514/263.2; 514/265.1 |
International
Class: |
A61K 39/395 20060101
A61K039/395; C07D 487/04 20060101 C07D487/04; C07D 471/04 20060101
C07D471/04; C07D 473/32 20060101 C07D473/32; A61K 31/5025 20060101
A61K031/5025; A61K 31/437 20060101 A61K031/437; A61K 31/52 20060101
A61K031/52; A61K 31/519 20060101 A61K031/519; A61P 25/28 20060101
A61P025/28 |
Claims
1-91. (canceled)
92. A compound of the formula (I): ##STR00238## selected from the
group consisting of compounds: ##STR00239## or a pharmaceutically
acceptable salt, ester, or solvate thereof, wherein: G.sup.1,
G.sup.2, G.sup.3, G.sup.4, W, R.sup.1, Ring (A), Ring (E), Ring
(F), G.sup.5, G.sup.6, G.sup.7, R.sup.9, and R.sup.10 are
independently selected; letters (A), (E) and (F) in the formulas
are reference letters to identify the rings; the dotted line
between G.sup.1 and G.sup.2 represents an optional bond; the
numbers (1), (2), (3), (4), and (5) are reference numbers to
identify positions of the Ring (A); G.sup.4 is at position (1),
G.sup.3 is at position (2), G.sup.2 is at position (3), G.sup.1 is
at position (4) and the N is at position (5); when G.sup.5 is bound
to G.sup.4 (formula IA) then G.sup.4 is a --C--, and when G.sup.5
is bound to G.sup.3 (formula IB) then G.sup.3 is a --C--; in said
Ring (E): (a) G.sup.3 is C, and G.sup.4 is C, or (b) G.sup.3 is N
and G.sup.4 is C and the double bond between G.sup.3 and G.sup.4 is
tautomerized to Ring (E), in said Ring (F): (a) G.sup.3 is C, and
G.sup.4 is C, or (b) G.sup.4 is N and G.sup.3 is C and the double
bond between G.sup.3 and G.sup.4 is tautomerized to Ring (F); said
Ring (E) or (F) is a 4 to 10 membered heteroaryl, aryl,
cycloalkenyl, or heterocycloalkenyl ring; when said Ring (E) or (F)
is a heterocycloalkenyl ring or a heteroaryl ring, said Ring
optionally comprises at least one other heteroatom selected from
the group consisting of: --NR.sup.2--, --O--, --S--, --S(O)--, and
--S(O).sub.2--; said Ring (E) or (F) is optionally substituted with
1 to 6 independently selected R.sup.21 substituents; d is 0 or 1; m
is 0 to 6; n is 1 to 5; p is 0 to 5; q is 0, 1 or 2, and each q is
independently selected; r is 1 to 3; t is 1 or 2; W is selected
from the group consisting of: --C(O)--, --S(O).sub.2--, --S(O)--,
and --C(.dbd.NR.sup.2)--; G.sup.1 is selected from the group
consisting of: a direct bond, --O--, --S--, --C(R.sup.21).sub.q--,
--N(R.sup.2).sub.d--, --C(O)--, S(O), S(O).sub.2,
--C(N(R.sup.2).sub.2)-- (wherein each R.sup.2 is independently
selected), and --C(.dbd.NR.sup.2)--; and with the provisos that:
(1) when the optional bond between G.sup.1 and G.sup.2 is absent
then G.sup.1 is not --C(N(R.sup.2).sub.2)--; and (2) when the
optional bond between G.sup.1 and G.sup.2 is present then: (a) q
for the --C(R.sup.21).sub.q group is 0 or 1 (and when q is 0 then
there is a H on the carbon), and (b) d for the --N(R.sup.2).sub.d--
group is 0 (and there is no H on the N due to the double bond
between G.sup.1 and G.sup.2; and (c) G.sup.1 is not a direct bond,
--O--, --S--, --C(O)--, --C(.dbd.NR.sup.2)--, --S(O).sub.2--, or
--S(O)--; G.sup.2 is selected from the group consisting of: a
direct bond, --O--, --S--, --C(R.sup.21).sub.q,
--N(R.sup.2).sub.d--, --C(O)--, S(O), S(O).sub.2,
--C(N(R.sup.2).sub.2)-- (wherein each R.sup.2 is independently
selected), and --C(.dbd.NR.sup.2)--; and with the provisos that:
(1) when the optional bond between G.sup.1 and G.sup.2 is absent
then G.sup.2 is not --C(N(R.sup.2).sub.2)--; and (2) when the
optional bond between G.sup.1 and G.sup.2 is present, then: (a) q
for the --C(R.sup.21).sub.q group is 0 or 1 (and when q is 0 then
there is a H on the carbon), and (b) d for the --N(R.sup.2).sub.d--
group is 0; and (c) G.sup.2 is not a direct bond, --O--, --S--,
--C(O)--, --C(.dbd.NR.sup.2)--)-, --S(O).sub.2--, or --S(O)--;
G.sup.5 is selected from the group consisting of: direct bond, CH,
--C(R.sup.21).sub.q, --N(R.sup.2).sub.d, --O--, --S--,
--S(O).sub.t; --C(O)--, --(C.dbd.NR.sup.2)--, --CHR.sup.3--,
C(R.sup.4).sub.2, --CF.sub.2--, --N(R.sup.2)--, --CR.sup.4(OH)--,
--CR.sup.4(OR.sup.4)--, cycloalkyl, and heterocycloalkyl; G.sup.6
is selected from the group consisting of: C, CR.sup.3, and N;
G.sup.7 is selected from the group consisting of: a direct bond,
--C(O)--, --(C.dbd.NR.sup.2)--, --CHR.sup.3--, C(R.sup.4).sub.2,
--CF.sub.2--, --N(R.sup.2)--, --O--, --S--, --S(O).sub.t,
--CR.sup.4(OH)--, --CR.sup.4(OR.sup.4)--, --C.dbd.C--, alkynyl,
--(CH.sub.2).sub.rN(R.sup.2)--, --(CHR.sup.4).sub.rN(R.sup.2)--,
--(C(R.sup.4).sub.2).sub.rN(R.sup.2)--,
--N(R.sup.2)(CH.sub.2).sub.r--, --N(R.sup.2)(CHR.sup.4).sub.r--,
--N(R.sup.2)(C(R.sup.4).sub.2).sub.r--, --(CH.sub.2).sub.r--O--,
--(CHR.sup.4).sub.r--O--, --(C(R.sup.4).sub.2).sub.r--O--,
--O--(CH.sub.2).sub.r--, --O--(CHR.sup.4).sub.r--,
--O--(C(R.sup.4).sub.2).sub.r--, --C(O)NR.sup.5--, --O--C(O)--,
--C(O)--O--, --O--C(O)--NR.sup.5--, --NR.sup.5C(O)--,
--(CH.sub.2).sub.rNR.sup.5--C(O)--,
--(CHR.sup.4).sub.rNR.sup.5--C(O)--,
--(C(R.sup.4).sub.2).sub.rNR.sup.5--C(O)--,
--C(O)NR.sup.5(CH.sub.2).sub.r--, --C(O)NR.sup.5
(CHR.sup.4).sub.r--, --C(O)NR.sup.5(C(R.sup.4).sub.2).sub.r--,
--NR.sup.5S(O).sub.t--, --(CH.sub.2).sub.rNR.sup.5S(O).sub.t--,
--(CHR.sup.4).sub.rNR.sup.5S(O).sub.t--,
--(C(R.sup.4).sub.2).sub.rNR.sup.5S(O).sub.t--,
--S(O).sub.tNR.sup.5--, --S(O).sub.tNR.sup.5(CH.sub.2).sub.r--,
--S(O).sub.tNR.sup.5(CHR.sup.4).sub.r--,
--S(O).sub.tNR.sup.5(C(R.sup.4).sub.2).sub.r--,
--NR.sup.5--C(O)--O--, --NR.sup.5--C(O)--NR.sup.5--,
--NR.sup.5--S(O).sub.t--NR.sup.5--,
--NR.sup.5--C(.dbd.NR.sup.2)--NR.sup.5--,
--NR.sup.5--C(.dbd.NR.sup.2)--O--,
--O--C(.dbd.NR.sup.2)--NR.sup.5--, --C(R.sup.4).dbd.N--O--,
--O--N.dbd.C(R.sup.4)--, --O--C(R.sup.4).dbd.N--,
--N.dbd.C(R.sup.4)--O--, --(CH.sub.2).sub.2--,
--(C(R.sup.4).sub.2).sub.2--, --(CHR.sup.4).sub.2--,
--(CH.sub.2).sub.3--, --(C(R.sup.4).sub.2).sub.3--,
--(CHR.sup.4).sub.3--, cycloalkyl, and heterocycloalkyl; provided
that 0 to 2 of the G.sup.1, G.sup.2, G.sup.3, and G.sup.4 moieties
are --N(R.sup.2).sub.d-- and each R.sup.2 is independently selected
and each d is independently selected, and provided that Ring (A)
does not have three consecutive ring nitrogen atoms; R.sup.1 is
selected from the group consisting of: alkyl-, alkenyl-, alkynyl-,
aryl-, arylalkyl-, alkylaryl-, cycloalkyl-, cycloalkenyl,
cycloalkylalkyl-, fused benzocycloalkyl, fused
benzoheterocycloalkyl, fused heteroarylcycloalkyl, fused
heteroarylheterocycloalkyl, fused cycloalkylaryl, fused
heterocycloalkylaryl, fused cycloalkylheteroaryl, fused
heterocycloalkylheteroaryl, fused benzocycloalkyl alkyl, fused
benzoheterocycloalkyl alkyl, fused heteroarylcycloalkyl alkyl,
fused heteroarylheterocycloalkyl alkyl, fused cycloalkylaryl alkyl,
fused heterocycloalkylaryl alkyl, fused cycloalkylheteroaryl alkyl,
fused heterocycloalkylheteroaryl alkyl, heteroaryl-,
heteroarylalkyl-, heterocyclyl-, heterocyclenyl, -and
heterocyclyalkyl-; wherein each of said alkyl-, alkenyl- and
alkynyl-, aryl-, arylalkyl-, alkylaryl-, cycloalkyl-,
cycloalkenyl-, cycloalkylalkyl-, fused benzocycloalkyl, fused
benzoheterocycloalkyl, fused heteroarylcycloalkyl, fused
heteroarylheterocycloalkyl, fused cycloalkylaryl, fused
heterocycloalkylaryl, fused cycloalkylheteroaryl, fused
heterocycloalkylheteroaryl, fused benzocycloalkyl alkyl, fused
benzoheterocycloalkyl alkyl, fused heteroarylcycloalkyl alkyl,
fused heteroarylheterocycloalkyl alkyl, fused cycloalkylaryl alkyl,
fused heterocycloalkylaryl alkyl, fused cycloalkylheteroaryl alkyl,
fused heterocycloalkylheteroaryl alkyl, heteroaryl-,
heteroarylalkyl-, heterocyclyl-, heterocyclenyl and
heterocyclyalkyl-R.sup.1 groups is optionally substituted with 1-5
independently selected R.sup.21 groups; Each R.sup.2 is
independently selected from the group consisting of: H, --OH,
--O-alkyl, --O-(halo substituted alkyl), --NH(R.sup.4),
--N(R.sup.4).sub.2, --NH.sub.2, --S(O)R.sup.4, --S(O)(OR.sup.4),
--S(O).sub.2R.sup.4, --S(O).sub.2(OR.sup.4), --S(O)NHR.sup.4,
--S(O)N(R.sup.4).sub.2, --S(O)NH.sub.2, --S(O).sub.2NHR.sup.4,
--S(O).sub.2N(R.sup.4).sub.2, --S(O).sub.2NH.sub.2, --CN,
--C(O).sub.2R.sup.4, --C(O)NHR.sup.4, --C(O)N(R.sub.4).sub.2,
--C(O)NH.sub.2, --C(O)R.sup.4, unsubstituted aryl, substituted
aryl, unsubstituted heteroaryl, substituted heteroaryl,
unsubstituted alkyl, substituted alkyl, unsubstituted arylalkyl-,
substituted arylalkyl-, unsubstituted heteroarylalkyl-, substituted
heteroarylalkyl-, unsubstituted alkenyl, substituted alkenyl,
unsubstituted alkynyl, substituted alkynyl, unsubstituted
cycloalkyl, and substituted cycloalkyl, wherein said substituted
aryl, heteroaryl, alkyl, arylalkyl-, heteroarylalkyl-, alkenyl,
alkynyl and cycloalkyl groups are substituted with 1 to 5
independently selected R.sup.21 groups; R.sup.3 is selected from
the group consisting of: H, --OH, halo, --O-alkyl, --O-(halo
substituted alky), --NH(R.sup.4), --N(R.sup.4).sub.2, --NH.sub.2,
--S(R.sup.4), --S(O)R.sup.4, --S(O)(OR.sup.4), --S(O).sub.2R.sup.4,
--S(O).sub.2(OR.sup.4), --S(O)NHR.sup.4, --S(O)N(R.sub.4).sub.2,
--S(O)NH.sub.2, --S(O).sub.2NHR.sup.4,
--S(O).sub.2N(R.sup.4).sub.2, --S(O).sub.2NH.sub.2, --CN,
--C(O).sub.2R.sup.4, --C(O)NHR.sup.4, --C(O)N(R.sup.4).sub.2,
--C(O)NH.sub.2, --C(O)R.sup.4, unsubstituted aryl, substituted
aryl, unsubstituted heteroaryl, substituted heteroaryl,
unsubstituted alkyl, substituted alkyl, unsubstituted arylalkyl-,
substituted arylalkyl-, unsubstituted heteroarylalkyl-, substituted
heteroarylalkyl-, unsubstituted alkenyl, substituted alkenyl,
unsubstituted alkynyl, substituted alkynyl, unsubstituted
cycloalkyl, and substituted cycloalkyl, wherein said substituted
aryl, heteroaryl, alkyl, arylalkyl-, heteroarylalkyl-, alkenyl,
alkynyl and cycloalkyl groups are substituted with 1 to 5
independently selected R.sup.21 groups; each R.sup.4 is
independently selected from the group consisting of: unsubstituted
aryl, substituted aryl, unsubstituted heteroaryl, substituted
heteroaryl, unsubstituted alkyl, substituted alkyl, unsubstituted
arylalkyl-, substituted arylalkyl-, unsubstituted heteroarylalkyl-,
substituted heteroarylalkyl-, unsubstituted alkenyl, substituted
alkenyl, unsubstituted alkynyl, substituted alkynyl, unsubstituted
cycloalkyl, and substituted cycloalkyl, wherein said substituted
aryl, heteroaryl, alkyl, arylalkyl-, heteroarylalkyl-, alkenyl,
alkynyl and cycloalkyl groups are substituted with 1 to 5
independently selected R.sup.21 groups; each R.sup.5 is
independently selected from the group consisting of: H,
unsubstituted alkyl, substituted alkyl, unsubstituted alkenyl,
substituted alkenyl, unsubstituted alkynyl, substituted alkynyl,
unsubstituted cycloalkyl, substituted cycloalkyl, unsubstituted
aryl, substituted aryl, unsubstituted heteroaryl and substituted
heteroaryl; wherein said substituted groups are substituted with
one or more substituents independently selected from: R.sup.2; Each
R.sup.6 is independently selected from the group consisting of: H,
halo, --CF.sub.3, --O-alkyl, --O-(halo substituted alky),
--S(O)R.sup.4, --S(O)(OR.sup.4), --S(O)NHR.sup.4,
--S(O)N(R.sup.4).sub.2 (wherein each R.sup.4 is independently
selected), --S(O)NH.sub.2, --S(O).sub.2NHR.sup.4,
--S(O).sub.2N(R.sup.4).sub.2 (wherein each R.sup.4 is independently
selected), --S(O).sub.2NH.sub.2, --C(.dbd.NOR.sup.24)R.sup.25, and
--S(O).sub.2R.sup.24; --CN, --C(O).sub.2R.sup.4, --C(O)NHR.sup.4,
--C(O)N(R.sup.4).sub.2 (wherein each R.sup.4 is independently
selected), --C(O)NH.sub.2, --C(O)R.sup.4, unsubstituted aryl,
substituted aryl, unsubstituted heteroaryl, substituted heteroaryl,
unsubstituted alkyl, substituted alkyl, unsubstituted arylalkyl-,
substituted arylalkyl-, unsubstituted heteroarylalkyl-, substituted
heteroarylalkyl-, unsubstituted alkenyl, substituted alkenyl,
unsubstituted alkynyl, substituted alkynyl, unsubstituted
cycloalkyl, and substituted cycloalkyl, wherein said substituted
aryl, heteroaryl, alkyl, arylalkyl-, heteroarylalkyl-, alkenyl,
alkynyl and cycloalkyl groups are substituted with 1 to 5
independently selected R.sup.21 groups; R.sup.9 is selected from
the group consisting of: arylalkoxy-, heteroarylalkoxy-,
arylalkylamino-, heteroarylalkylamino-, aryl, arylalkyl-,
heteroaryl, heteroarylalkyl-, heterocyclyl, heterocyclenyl, and
heterocyclyalkyl-, wherein each of said R.sup.9 arylalkoxy-,
heteroarylalkoxy-, arylalkylamino-, heteroarylalkylamino-, aryl,
arylalkyl-, heteroaryl, heteroarylalkyl-, heterocyclyl,
heterocyclenyl, and heterocyclyalkyl- is optionally substituted
with 1-5 independently selected R.sup.21 groups; R.sup.10 is
selected from the group consisting of: aryl-, heteroaryl-,
cycloalkyl-, cycloalkenyl, cycloalkylalkyl-, heterocyclyl-,
heterocyclenyl-, heterocyclylalkyl-, heterocyclyalkenyl-, fused
benzocycloalkyl-, fused benzoheterocycloalkyl-, fused
heteroarylcycloalkyl-, fused heteroarylheterocycloalkyl-, fused
cycloalkylaryl, fused heterocycloalkylaryl-, fused
cycloalkylheteroaryl-, fused heterocycloalkylheteroaryl-,
##STR00240## ##STR00241## wherein X is selected from the group
consisting of: O, --N(R.sup.14)-- and --S--; and wherein each of
said R.sup.10 moieties is optionally substituted with 1-5
independently selected R.sup.21 groups; or R.sup.9 and R.sup.10 are
linked together to form a fused tricyclic ring system wherein
R.sup.9 and R.sup.10 are as defined above and the ring linking
R.sup.9 and R.sup.10 is an alkyl ring, or a heteroalkyl ring, or an
aryl ring, or a heteroaryl ring, or an alkenyl ring, or a
heteroalkenyl ring (for example, the tricyclic ring system is
formed by linking the atoms adjacent to the atoms by which R.sup.9
and R.sup.10 are bound together); R.sup.14 is selected from the
group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl,
cycloalkylalkyl, cycloalkenyl, heterocyclyl, heterocyclenyl,
heterocyclylalkyl, heterocyclyalkenyl-, aryl, arylalkyl,
heteroaryl, heteroarylalkyl, --CN, --C(O)R.sup.15, --C(O)OR.sup.15,
--C(O)N(R.sup.15)(R.sup.16), --S(O)N(R.sup.15)(R.sup.16),
--S(O).sub.2N(R.sup.15)(R.sup.16), --C(.dbd.NOR.sup.15)R.sup.16,
and --P(O)(OR.sup.15)(OR.sup.16); R.sup.15A and R.sup.16A are
independently selected from the group consisting of alkyl, alkenyl,
alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl,
heterocyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,
arylcycloalkyl, arylheterocyclyl, (R.sup.18).sub.n-alkyl,
(R.sup.18).sub.n-cycloalkyl, (R.sup.18).sub.n-cycloalkylalkyl,
(R.sup.18).sub.n-heterocyclyl, (R.sup.18).sub.n-heterocyclylalkyl,
(R.sup.18).sub.n-aryl, (R.sup.18).sub.n-arylalkyl,
(R.sup.18).sub.n-heteroaryl and (R.sup.18).sub.n-heteroarylalkyl;
or R.sup.15, R.sup.16 and R.sup.17 are independently selected from
the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl,
cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl,
heteroaryl, heteroarylalkyl, arylcycloalkyl, arylheterocyclyl,
(R.sup.18).sub.n-alkyl, (R.sup.18).sub.n-cycloalkyl,
(R.sup.18).sub.n-cycloalkylalkyl, (R.sup.18).sub.n-heterocyclyl,
(R.sup.18).sub.n-heterocyclylalkyl, (R.sup.18).sub.n-aryl,
(R.sup.18).sub.n-arylalkyl, (R.sup.18).sub.n-heteroaryl and
(R.sup.18).sub.n-heteroarylalkyl; each R.sup.18 is independently
selected from the group consisting of alkyl, alkenyl, alkynyl,
aryl, arylalkyl, arylalkenyl, arylalkynyl, --NO.sub.2, halo,
heteroaryl, HO-alkyoxyalkyl, --CF.sub.3, --CN, alkyl-CN,
--C(O)R.sup.19, --C(O)OH, --C(O)OR.sup.19, --C(O)NHR.sup.20,
--C(O)NH.sub.2, --C(O)NH.sub.2--C(O)N(alkyl).sub.2,
--C(O)N(alkyl)(aryl), --C(O)N(alkyl)(heteroaryl), --SR.sup.19,
--S(O).sub.2R.sup.20, --S(O)NH.sub.2, --S(O)NH(alkyl),
--S(O)N(alkyl)(alkyl), --S(O)NH(aryl), --S(O).sub.2NH.sub.2,
--S(O).sub.2NHR.sup.19, --S(O).sub.2NH(heterocyclyl),
--S(O).sub.2N(alkyl).sub.2, --S(O).sub.2N(alkyl)(aryl),
--OCF.sub.3, --OH, --OR.sup.20, --O-heterocyclyl,
--O-cycloalkylalkyl, --O-heterocyclylalkyl, --NH.sub.2,
--NHR.sup.20, --N(alkyl).sub.2, --N(arylalkyl).sub.2,
--N(arylalkyl)-(heteroarylalkyl), --NHC(O)R.sup.20,
--NHC(O)NH.sub.2, --NHC(O)NH(alkyl), --NHC(O)N(alkyl)(alkyl),
--N(alkyl)C(O)NH(alkyl), --N(alkyl)C(O)N(alkyl)(alkyl),
--NHS(O).sub.2R.sup.20, --NHS(O).sub.2NH(alkyl),
--NHS(O).sub.2N(alkyl)(alkyl), --N(alkyl)S(O).sub.2NH(alkyl) and
--N(alkyl)S(O).sub.2N(alkyl)(alkyl); or two R.sup.18 moieties on
adjacent carbons can be linked together to form a ##STR00242##
R.sup.19 is selected from the group consisting of: alkyl,
cycloalkyl, aryl, arylalkyl and heteroarylalkyl; R.sup.20 is
selected from the group consisting of: alkyl, cycloalkyl, aryl,
halo substituted aryl, arylalkyl, heteroaryl and heteroarylalkyl;
each R.sup.21 is independently selected from the group consisting
of: alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl,
cycloalkenyl, heterocycloalkyl, .dbd.O, .dbd.N--R.sup.2,
heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl,
heteroarylalkyl, halo, --CN, --OR.sup.15, --C(O)R.sup.15,
--C(O)OR.sup.15, --C(O)N(R.sup.15)(R.sup.16), --SR.sup.15,
--P(O)(CH.sub.3).sub.2, --SO(.dbd.NR.sup.15)R.sup.16--, --SF.sub.5,
--OSF.sub.5, --Si(R.sup.15A).sub.3 wherein each R.sup.15A is
independently selected --S(O)N(R.sup.15)(R.sup.16),
--CH(R.sup.15)(R.sup.16), --S(O).sub.2N(R.sup.15)(R.sup.16),
--C(.dbd.NOR.sup.15)R.sup.16, --P(O)(OR.sup.15)(OR.sup.16),
--N(R.sup.15)(R.sup.16), -alkyl-N(R.sup.15)(R.sup.16),
--N(R.sup.15)C(O)R.sup.16, --CH.sub.2N(R.sup.15)C(O)R.sup.16,
--CH.sub.2--N(R.sup.15)C(O)N(R.sup.16)(R.sup.17),
--CH.sub.2--R.sup.15; --CH.sub.2N(R.sup.15)(R.sup.16),
--N(R.sup.15)S(O)R.sup.16A, --N(R.sup.15)S(O).sub.2R.sup.16A,
--CH.sub.2--N(R.sup.15)S(O).sub.2R.sup.16A,
--N(R.sup.15)S(O).sub.2N(R.sup.16)(R.sup.17),
--N(R.sup.15)S(O)N(R.sup.16)(R.sup.17),
--N(R.sup.15)C(O)N(R.sup.16)(R.sup.17),
--CH.sub.2--N(R.sup.15)C(O)N(R.sup.16)(R.sup.17),
--N(R.sup.15)C(O)OR.sup.16, --CH.sub.2--N(R.sup.15)C(O)OR.sup.16,
--S(O)R.sup.15A, .dbd.NOR.sup.15, --N.sub.3, --NO.sub.2,
--S(O).sub.2R.sup.15A, --O--N.dbd.C(R.sup.4).sub.2 (wherein each
R.sup.4 is independently selected), and --O--N.dbd.C(R.sup.4).sub.2
wherein R.sup.4 is taken together with the carbon atom to which
they are bound to form a 5 to 10 membered ring, said ring
optionally containing 1 to 3 heteroatoms selected from the group
consisting of --O--, --S--, --S(O)--, --S(O).sub.2--, and
--NR.sup.2--; wherein each of said alkyl, alkenyl, alkynyl,
cycloalkyl, cycloalkylalkyl, cycloalkenyl, heterocycloalkyl,
heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, and
heteroarylalkyl R.sup.21 groups is optionally substituted with 1 to
5 independently selected R.sup.22 groups; each R.sup.22 group is
independently selected from the group consisting of alkyl,
cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, heteroaryl, halo,
--CF.sub.3, --CN, --OR.sup.15, --C(O)R.sup.15, --C(O)OR.sup.15,
-alkyl-C(O)OR.sup.15, C(O)N(R.sup.15)(R.sup.16), --SR.sup.15,
--S(O)N(R.sup.15)(R.sup.16), --S(O).sub.2N(R.sup.15)(R.sup.16),
--C(.dbd.NOR.sup.15)R.sup.16, --P(O)(OR.sup.15)(OR.sup.16),
--N(R.sup.15)(R.sup.16), -alkyl-N(R.sup.15)(R.sup.16),
--N(R.sup.15)C(O)R.sup.16, --CH.sub.2--N(R.sup.15)C(O)R.sup.16,
--N(R.sup.15)S(O)R.sup.16A, --N(R.sup.15)S(O).sub.2R.sup.16A,
--CH.sub.2--N(R.sup.15)S(O).sub.2R.sup.16A,
--N(R.sup.15)S(O).sub.2N(R.sup.16)(R.sup.17),
--N(R.sup.15)S(O)N(R.sup.16)(R.sup.17),
--N(R.sup.15)C(O)N(R.sup.16)(R.sup.17),
--CH.sub.2--N(R.sup.15)C(O)N(R.sup.16)(R.sup.17),
--N(R.sup.15)C(O)OR.sup.16, --CH.sub.2--N(R.sup.15)C(O)OR.sup.16,
--N.sub.3, .dbd.NOR.sup.15, --NO.sub.2, --S(O)R.sup.15A and
--S(O).sub.2R.sup.15A; and provided that: Ring (A) does not have
any --S--S--, --S--S(O)--, --S--S(O).sub.2--, --S(O)--S(O)--,
--S(O)--S(O).sub.2--, or --S(O).sub.2--S(O).sub.2-- bonds in the
ring; Ring (A) does not have any --O--O-- bonds in the ring; Ring
(A) does not have any --O--S--, --O--S(O)--, or --O--S(O).sub.2--
bonds in the ring; Ring (A) does not have any --N--S--N-- bonds in
the ring; Ring (A) does not have any --N--O--N-- bonds in the ring;
and Ring (A) does not have three adjacent nitrogent atoms in the
ring.
93. The compound of claim 92, wherein R.sup.9 is selected from the
group consisting of: 1gg to 13gg.
94. The compound of claim 92, wherein the R.sup.9-R.sup.10-moiety
is selected from the group consisting of: 1bb to 40bb.
95. The compound of claim 92, wherein R.sup.1 is selected from the
group consisting of: ##STR00243## ##STR00244##
96. The compound of claim 92, wherein R.sup.1 is phenyl substituted
with 1 to 3 independently selected R.sup.21 moieties wherein at
least one R.sup.21 moiety is selected from the group consisting of
--SF.sub.5, --OSF.sub.5 and --Si(R.sup.15A).sub.3.
97. The compound of claim 92, wherein the R.sup.9-R.sup.10-moiety
is: ##STR00245##
98. The compound of claim 92, wherein R.sup.1 is an alkyl group
substituted with a group selected from the group consisting of:
##STR00246## ##STR00247##
99. The compound of claim 92, wherein R.sup.1 is an alkyl group
substituted with a phenyl that is substituted with 1-3 halos
independently selected from the group consisting of F and Cl; or
R.sup.1 is an alkyl group substituted with a phenyl that is
substituted with 1 to 3 independently selected R.sup.21 moieties
wherein at least one R.sup.21 moiety is selected from the group
consisting of --SF.sub.5, --OSF.sub.5 and
--Si(R.sup.15A).sub.3.
100. The compound of claim 92, wherein said R.sup.10 is selected
from the group consisting of aryl and aryl substituted with one or
more R.sup.21 groups, and said R.sup.9 group is selected from the
group consisting of heteroaryl and heteroaryl substituted with one
or more R.sup.21 groups, wherein each R.sup.21 is independently
selected; or said R.sup.10 is phenyl substituted with one R.sup.21
group, and said R.sup.9 is imidazolyl substituted with one R.sup.21
group, wherein each R.sup.21 is independently selected.
101. The compound of claim 92, wherein the R.sup.9-R.sup.10-moiety
is: ##STR00248## or wherein the R.sup.9-R.sup.10-moiety is:
##STR00249## or wherein the R.sup.9-R.sup.10-moiety is:
##STR00250## or wherein the R.sup.9-R.sup.10-moiety is:
##STR00251## or wherein the R.sup.9-R.sup.10-moiety is:
##STR00252## or wherein the R.sup.9-R.sup.10-moiety is:
##STR00253##
102. The compound of claim 92, wherein said R.sup.1 group is:
##STR00254## wherein R.sup.21 is unsubstituted or substituted with
one or more independently selected R.sup.22 groups; or R.sup.1 is
an alkyl group substituted with one R.sup.21 group, and said
R.sup.21 group is an aryl group; or R.sup.1 is an alkyl group
substituted with one R.sup.21 group, and said R.sup.21 group is an
aryl group, and said aryl is phenyl, and said alkyl group is methyl
or ethyl; or R.sup.1 is an alkyl group substituted with one
R.sup.21 group, and said R.sup.21 group is an aryl group, and said
aryl group is substituted with one or more R.sup.22 groups; or
R.sup.1 is an alkyl group substituted with one R.sup.21 group, and
said R.sup.21 group is an aryl group, and said aryl group is
substituted with one or more R.sup.22 groups wherein each R.sup.22
group is the same or different halo; or R.sup.1 is an alkyl group
substituted with one R.sup.21 group, and said R.sup.21 group is an
aryl group, and said aryl group is substituted with one or two
R.sup.22 halo groups; or R.sup.1 is an alkyl group substituted with
one R.sup.21 group, and said R.sup.21 group is an aryl group, and
said aryl group is substituted with one or two R.sup.22 halo groups
wherein the halo is F; or R.sup.1 is an alkyl group substituted
with one R.sup.21 group, and said R.sup.21 group is an aryl group,
and said aryl group is substituted with three R.sup.22 halo groups;
or R.sup.1 is an alkyl group substituted with one R.sup.21 group,
and said R.sup.21 group is an aryl group, and said aryl group is
substituted with three R.sup.22 halo groups wherein the halo is
F.
103. The compound of claim 92, wherein said R.sup.1 is selected
from the group consisting of: ##STR00255##
104. The compound of claim 92, wherein said R.sup.10 is selected
from the group consisting of heteroaryl and heteroaryl substituted
with one or more R.sup.21 groups, and said R.sup.9 group is
selected from the group consisting of heteroaryl and heteroaryl
substituted with one or more R.sup.21 groups, and wherein each
R.sup.21 is independently selected.
105. The compound of claim 92, wherein: (1) R.sup.1 is an alkyl
group substituted with one R.sup.21 group, or R.sup.1 is an alkyl
group substituted with one R.sup.21 group, and said R.sup.21 group
is substituted with one or more independently selected R.sup.22
groups, and R.sup.10 is selected from the group consisting of aryl
and aryl substituted with one or more independently selected
R.sup.21 groups, and R.sup.9 is selected from the group consisting
of heteroaryl and heteroaryl substituted with one or more
independently selected R.sup.21 groups; or (2) R.sup.1 is an alkyl
group substituted with one phenyl, or R.sup.1 is an alkyl group
substituted with one phenyl, and said phenyl is substituted with
one or more independently selected R.sup.22 groups, and R.sup.10 is
selected from the group consisting of phenyl and phenyl substituted
with one or more independently selected R.sup.21 groups, and
R.sup.9 is selected from the group consisting of imidazolyl and
imidazolyl substituted with one or more independently selected
R.sup.21 groups; or (3) R.sup.1 is a methyl or ethyl group
substituted with one phenyl, or R.sup.1 is a methyl or ethyl group
substituted with one phenyl, and said phenyl is substituted with
one or more independently selected halos, and R.sup.10 is selected
from the group consisting of phenyl and phenyl substituted with one
or more independently selected --OR.sup.15 groups, and R.sup.9 is
selected from the group consisting of imidazolyl and imidazolyl
substituted with one or more independently selected alkyl groups
groups; or (4) R.sup.1 is a methyl or ethyl group substituted with
one phenyl, or R.sup.1 is an methyl or ethyl group substituted with
one phenyl, and said phenyl is substituted with one or two
independently selected halos, and R.sup.10 is selected from the
group consisting of phenyl and phenyl substituted with one or two
independently selected --OR.sup.15 groups, wherein R.sup.15 is
alkyl, and R.sup.9 is selected from the group consisting of
imidazolyl and imidazolyl substituted with one or two independently
selected alkyl groups groups; or (5) R.sup.1 is a methyl or ethyl
group substituted with one phenyl, or R.sup.1 is an methyl or ethyl
group substituted with one phenyl, and said phenyl is substituted
with one or two F, and R.sup.10 is selected from the group
consisting of phenyl and phenyl substituted with one or two
independently selected --OR.sup.15 groups, wherein R.sup.15 is
methyl, and R.sup.9 is selected from the group consisting of
imidazolyl and imidazolyl substituted with one or two independently
selected methyl groups groups; or (6) R.sup.1 is a methyl or ethyl
group substituted with one phenyl, or R.sup.1 is an methyl or ethyl
group substituted with one phenyl, and said phenyl is substituted
with one or two F, and R.sup.10 is phenyl substituted with one
--OR.sup.15 group, wherein R.sup.15 is methyl, and R.sup.9 is
selected from the group consisting of imidazolyl and imidazolyl
substituted with one methyl group; or (7) R.sup.1 is a methyl or
ethyl group substituted with one phenyl, or R.sup.1 is an methyl or
ethyl group substituted with one phenyl, and said phenyl is
substituted with three F, and R.sup.10 is phenyl substituted with
one --OR.sup.15 group, wherein R.sup.15 is methyl, and R.sup.9 is
selected from the group consisting of imidazolyl and imidazolyl
substituted with one methyl group; or (8) R.sup.1 is an methyl or
ethyl group substituted with one phenyl, and said phenyl is
substituted with one or two F, and R.sup.10 is phenyl substituted
with one --OR.sup.15 group, wherein R.sup.15 is methyl, and R.sup.9
is selected from the group consisting of imidazolyl and imidazolyl
substituted with one methyl group; or (9) R.sup.1 is an methyl or
ethyl group substituted with one phenyl, and said phenyl is
substituted with three F, and R.sup.10 is phenyl substituted with
one --OR.sup.15 group, wherein R.sup.15 is methyl, and R.sup.9 is
selected from the group consisting of imidazolyl and imidazolyl
substituted with one methyl group; or (10) R.sup.1 is a methyl or
ethyl group substituted with one phenyl, or R.sup.1 is an methyl or
ethyl group substituted with one phenyl, and said phenyl is
substituted with one or two independently selected halos, and
R.sup.10 is selected from the group consisting of phenyl and phenyl
substituted with one or two independently selected R.sup.21 halo
groups, and R.sup.9 is selected from the group consisting of
imidazolyl and imidazolyl substituted with one or two independently
selected alkyl groups groups; or (11) R.sup.1 is a methyl or ethyl
group substituted with one phenyl, or R.sup.1 is an methyl or ethyl
group substituted with one phenyl, and said phenyl is substituted
with one or two independently selected halos, and R.sup.10 is
selected from the group consisting of phenyl and phenyl substituted
with one R.sup.21 halo group, and R.sup.9 is selected from the
group consisting of imidazolyl and imidazolyl substituted with one
or two independently selected alkyl groups groups; or (12) R.sup.1
is a methyl or ethyl group substituted with one phenyl, or R.sup.1
is an methyl or ethyl group substituted with one phenyl, and said
phenyl is substituted with one or two independently selected halos,
and R.sup.10 is selected from the group consisting of phenyl and
phenyl substituted with one R.sup.21 halo group, and said R.sup.21
group is F, and R.sup.9 is selected from the group consisting of
imidazolyl and imidazolyl substituted with one or two independently
selected alkyl groups groups; or (13) R.sup.1 is a methyl or ethyl
group substituted with one phenyl, or R.sup.1 is an methyl or ethyl
group substituted with one phenyl, and said phenyl is substituted
with one or two independently selected halos, and R.sup.10 is
selected from the group consisting of phenyl and phenyl substituted
with one R.sup.21 group and said R.sup.21 is an --OR.sup.15 group,
and R.sup.15 is an (R.sup.18).sub.nalkyl group, and R.sup.18 is
halo, and n is 1 to 3, and each halo is independently selected, and
R.sup.9 is selected from the group consisting of imidazolyl and
imidazolyl substituted with one or two independently selected alkyl
groups groups; or (14) R.sup.1 is a methyl or ethyl group
substituted with one phenyl, or R.sup.1 is an methyl or ethyl group
substituted with one phenyl, and said phenyl is substituted with
one or two independently selected halos, and R.sup.10 is phenyl
substituted with one R.sup.21 group and said R.sup.21 is an
--OR.sup.15 group, and R.sup.15 is an (R.sup.18).sub.nalkyl group,
and R.sup.18 is F, and n is 3, and R.sup.9 is selected from the
group consisting of imidazolyl and imidazolyl substituted with one
or two independently selected alkyl groups groups; or (15) R.sup.1
is a methyl or ethyl group substituted with one phenyl, or R.sup.1
is an methyl or ethyl group substituted with one phenyl, and said
phenyl is substituted with one or two independently selected halos,
and R.sup.10 is phenyl substituted with one R.sup.21 group and said
R.sup.21 is an --OR.sup.15 group, and R.sup.15 is an
(R.sup.18).sub.nalkyl group, and R.sup.18 is F, and n is 3, and the
alkyl group is methyl, and R.sup.9 is selected from the group
consisting of imidazolyl and imidazolyl substituted with one or two
independently selected alkyl groups groups; or (16) R.sup.1 is
selected from the group consisting of: ##STR00256## wherein the
R.sup.9-R.sup.10-moiety is: ##STR00257## or (17) R.sup.1 is
selected from the group consisting of: ##STR00258## and wherein the
R.sup.9-R.sup.10-moiety is: ##STR00259## or (18) R.sup.1 is
selected from the group consisting of: ##STR00260## and wherein the
R.sup.9-R.sup.10-moiety is: ##STR00261## or (19) R.sup.1 is
selected from the group consisting of: ##STR00262## and wherein the
R.sup.9-R.sup.10-moiety is: ##STR00263## or (20) R.sup.1 is
selected from the group consisting of: ##STR00264## and wherein the
R.sup.9-R.sup.10-moiety is: ##STR00265##
106. The compound of claim 92, wherein G.sup.5 is selected from the
group consisting of --CH--, --NH--, --N.dbd., --O--, and --S--; or
G.sup.5 is selected from the group consisting of --CH--, --NH--,
--N.dbd., --O--, and --S--, and G.sup.6 is selected from the group
consisting of: C and CH.
107. The compound of claim 92 selected from the group consisting
of: IA, IB, IA.1, IB, 43A to 54A, 43 to 54, 85.1, 88.1, 91.1, and
100 to 124.
108. A pharmaceutical composition: (1) comprising a therapeutically
effective amount of at least one compound of claim 92, or a
pharmaceutically acceptable salt, solvate, or ester thereof, and at
least one pharmaceutically acceptable carrier; or (2) comprising a
therapeutically effective amount of at least one compound of claim
92, or a pharmaceutically acceptable salt, solvate, or ester
thereof, and at least one pharmaceutically acceptable carrier, and
an effective amount of one or more BACE inhibitors; or (3)
comprising a therapeutically effective amount of at least one
compound of claim 92, or a pharmaceutically acceptable salt,
solvate, or ester thereof, and at least one pharmaceutically
acceptable carrier, and effective amount of one or more
cholinesterase inhibitors, or (4) comprising a therapeutically
effective amount of at least one compound of claim 92, or a
pharmaceutically acceptable salt, solvate, or ester thereof, and at
least one pharmaceutically acceptable carrier, and effective amount
of one or more pharmaceutically active ingredients selected from
the group consisting of BACE inhibitors, muscarinic antagonists,
cholinesterase inhibitors; gamma secretase inhibitors; gamma
secretase modulators; HMG-CoA reductase inhibitors; non-steroidal
anti-inflammatory agents; N-methyl-D-aspartate receptor
antagonists; anti-amyloid antibodies; vitamin E; nicotinic
acetylcholine receptor agonists; CB1 receptor inverse agonists or
CB1 receptor antagonists; an antibiotic; growth hormone
secretagogues; histamine H3 antagonists; AMPA agonists; PDE4
inhibitors; GABA.sub.A inverse agonists; inhibitors of amyloid
aggregation; glycogen synthase kinase beta inhibitors; promoters of
alpha secretase activity; PDE-10 inhibitors and cholesterol
absorption inhibitors, or (5) comprising a therapeutically
effective amount of at least one compound of claim 92, or a
pharmaceutically acceptable salt, solvate, or ester thereof, and at
least one pharmaceutically acceptable carrier, and an effective
amount of donepezil hydrochloride.
109. A method for treating Alzheimer's Disease, the method
comprising administering to a patient in need thereof a
therapeutically effective amount of a compound according to claim
92 or a pharmaceutically acceptable salt thereof.
110. A method for inhibiting the deposition of amyloid protein in,
on or around neurological tissue, the method comprising
administering to a patient in need thereof an effective amount of a
compound according to claim 92.
Description
REFERENCE TO RELATED APPLICATION
[0001] This application claims the benefit of U.S. Provisional
Application Ser. No. 61/012,857 filed Dec. 11, 2007.
FIELD OF THE INVENTION
[0002] The present invention relates to certain heterocyclic
compounds useful as gamma secretase modulators (including
inhibitors, antagonists and the like), pharmaceutical compositions
containing the compounds, and methods of treatment using the
compounds and compositions to treat various diseases including
central nervous system disorders such as, for example,
neurodegenerative diseases such as Alzheimer's disease and other
diseases relating to the deposition of amyloid protein. They are
especially useful for reducing Amyloid beta (hereinafter referred
to as A.beta.) production which is effective in the treatment of
diseases caused by A.beta. such as, for example, Alzheimers and
Down Syndrome.
BACKGROUND OF THE INVENTION
[0003] Alzheimer's disease is a disease characterized by
degeneration and loss of neurons and also by the formation of
senile plaques and neurofibrillary change. Presently, treatment of
Alzheimer's disease is limited to symptomatic therapies with a
symptom-improving agent represented by an acetylcholinesterase
inhibitor, and the basic remedy which prevents progress of the
disease has not been developed. A method of controlling the cause
of onset of pathologic conditions needs to be developed for
creation of the basic remedy of Alzheimer's disease.
[0004] A.beta. protein, which is a metabolite of amyloid precursor
protein (hereinafter referred to as APP), is considered to be
greatly involved in degeneration and loss of neurons as well as
onset of demential conditions (for example, see Klein W L, et al
Proceeding National Academy of Science USA, Sep. 2, 2003, 100(18),
p. 10417-22, suggest a molecular basis for reversible memory
loss.
[0005] Nitsch R M, and 16 others, Antibodies against .beta.-amyloid
slow cognitive decline in Alzheimer's disease, Neuron, May 22,
2003, 38(4), p. 547-554) suggest that the main components of
A.beta. protein are A.beta.40 consisting of 40 amino acids and
A.beta.42 having two additional amino acids at the C-terminal. The
A.beta.40 and A.beta.42 tend to aggregate (for example, see Jarrell
J T et al, The carboxy terminus of the .beta. amyloid protein is
critical for the seeding of amyloid formation: implications for the
pathogenesis of Alzheimer's disease, Biochemistry, May 11, 1993,
32(18), p. 4693-4697) and constitute the main components of senile
plaques (for example, (Glenner G G, et al, Alzheimer's disease:
initial report of the purification and characterization of a novel
cerebrovascular amyloid protein, Biochemical and Biophysical
Research Communications, May 16, 1984, 120(3), p. 885-90. See also
Masters C L, et al, Amyloid plaque core protein in Alzheimer
disease and Down syndrome, Proceeding National Academy of Science
USA, June 1985, 82(12), p. 4245-4249.).
[0006] Furthermore, it is known that mutations of APP and
presenelin genes, which is are observed in familial Alzheimer's
disease, increase production of A.beta.40 and A.beta.42 (for
example, see Gouras G K, et al, Intraneuronal A.beta.142
accumulation in human brain, American Journal of Pathology, January
2000, 156(1), p. 15-20. Also, see Scheuner I D, et al, Nature
Medicine, August 1996, 2(8), p. 864-870; and Forman M S, et al,
Differential effects of the Swedish mutant amyloid precursor
protein on .beta.-amyloid accumulation and secretion in neurons and
normeuronal cells, Journal of Biological Chemistry, Dec. 19, 1997,
272(51), p. 32247-32253.). Therefore, compounds which reduce
production of A.beta.40 and A.beta.42 are expected to be agents for
controlling progress of Alzheimer's disease or for preventing the
disease.
[0007] These A.beta.s are produced when APP is cleaved by beta
secretase and subsequently cleaved by gamma secretase. In
consideration of this, creation of inhibitors of .gamma.-secretase
and .beta.-secretase has been attempted for the purpose of reducing
production of A.beta.s. Many of these known secretase inhibitors
are peptides or peptidomimetics such as L-685,458. L-685,458, an
aspartyl protease transition state mimic, is a potent inhibitor of
.gamma.-secretase activity, Biochemistry, Aug. 1, 2000, 39(30), p,
8698-8704).
[0008] Also of interest in connection with the present invention
are: US 2007/0117798 (Eisai, published May 24, 2007); US
2007/0117839 (Eisai, published May 24, 2007); US 2006/0004013
(Eisai, published Jan. 5, 2006); WO 2005/110422 (Boehringer
Ingeiheim, published Nov. 24, 2005); WO 2006/045554 (Cellzone AG,
published May 4, 2006); WO 2004/110350 (Neurogenetics, published
Dec. 23, 2004); WO 2004/071431 (Myriad Genetics, published Aug. 26,
2004); US 200510042284 (Myriad Genetics, published Feb. 23, 2005)
and WO 2006/001877 (Myriad Genetics, published Jan. 5, 2006).
[0009] There is a need for new compounds, formulations, treatments
and therapies to treat diseases and disorders associated with
A.beta.. It is, therefore, an object of this invention to provide
compounds useful in the treatment or prevention or amelioration of
such diseases and disorders.
SUMMARY OF THE INVENTION
[0010] In its many embodiments, the present invention provides a
novel class of compounds as gamma secretase modulators (including
inhibitors, antagonists and the like), methods of preparing such
compounds, pharmaceutical compositions comprising one or more such
compounds, methods of preparing pharmaceutical formulations
comprising one or more such compounds, and methods of treatment,
prevention, inhibition or amelioration of one or more diseases
associated with the A.beta. using such compounds or pharmaceutical
compositions.
[0011] This invention provides novel compounds, that are gamma
secretase modulators, of the formula:
##STR00002##
or a pharmaceutically acceptable salt, ester, or solvate thereof,
wherein: [0012] (1) Ring (E) comprises the moiety
##STR00003##
[0012] wherein G.sup.5 is bound to G.sup.4, and the rest of Ring
(E) is formed between G.sup.6 and G.sup.3, and [0013] (2) Ring (F)
comprises the moiety
##STR00004##
[0013] wherein G.sup.5 is bound to G.sup.3, and the rest of Ring
(F) is formed between G.sup.6 and G.sup.4, and [0014] (3) G.sup.1,
G.sup.2, G.sup.3, G, W, R.sup.1, Ring (A), Ring (E), Ring (F),
G.sup.5, G.sup.6, G.sup.7, R.sup.9, and R.sup.10 are independently
selected and are as defined below for formulas (IA) and (IB).
[0015] Thus, this invention provides novel compounds of formula
(I)
##STR00005##
selected from the group consisting of:
##STR00006##
or a pharmaceutically acceptable salt, ester, or solvate thereof,
wherein all substituents are defined below.
[0016] This invention also provides compounds of formula (I).
[0017] This invention also provides compounds of formula (I) in
pure and isolated form.
[0018] This invention also provides compounds of formula (I)
selected from the group consisting of: compounds of formulas IA,
IB, IA.1, IB.1, 43A to 54A, 43 to 54, 85.1, 88.1, 91.1, and 100 to
124.
[0019] This invention also provides compounds of formula (I)
selected from the group consisting of: compounds of formulas 43A to
54A, 43 to 54, 85.1, 88.1, 91.1, and 100 to 124.
[0020] This invention also provides compounds of formula (I)
selected from the group consisting of: compounds of formulas IA,
IB, IA.1, and IB.1.
[0021] This invention also provides compounds of formula (I)
selected from the group consisting of: compounds of formulas 43A to
54A.
[0022] This invention also provides compounds of formula (I)
selected from the group consisting of: compounds of formulas 43 to
54.
[0023] This invention also provides compounds of formula (I)
selected from the group consisting of: compounds of formulas 85.1,
88.1, 91.1, and 100 to 124.
[0024] This invention also provides pharmaceutical compositions
comprising an effective amount of one or more (e.g., one) compounds
of formula (I), or a pharmaceutically acceptable salt, ester or
solvate thereof, and a pharmaceutically acceptable carrier.
[0025] This invention also provides pharmaceutical compositions
comprising an effective amount of one or more (e.g., one) compounds
of formula (I), or a pharmaceutically acceptable salt, ester or
solvate thereof, and an effective amount of one or more (e.g., one)
other pharmaceutically active ingredients (e.g., drugs), and a
pharmaceutically acceptable carrier.
[0026] The compounds of formula (I) can be useful as gamma
secretase modulators and can be useful in the treatment and
prevention of diseases such as, for example, central nervous system
disorders such as Alzheimers disease and Downs Syndrome.
[0027] Thus, this invention also provides methods for: (1) method
for modulating (including inhibiting, antagonizing and the like)
gamma-secretase; (2) treating one or more neurodegenerative
diseases; (3) inhibiting the deposition of amyloid protein (e.g.,
amyloid beta protein) in, on or around neurological tissue (e.g.,
the brain); (4) Alzheimer's disease; and (5) treating Downs
syndrome; wherein each method comprises administering an effective
amount of one or more (e.g., one) compounds of formula (I) to a
patient in need of such treatment.
[0028] This invention also provides combination therapies for (1)
modulating gamma-secretase, or (2) treating one or more
neurodegenerative diseases, or (3) inhibiting the deposition of
amyloid protein (e.g., amyloid beta protein) in, on or around
neurological tissue (e.g., the brain), or (4) treating Alzheimer's
disease. The combination therapies are directed to methods
comprising the administration of an effective amount of one or more
(e.g. one) compounds of formula (I) and the administration of an
effective amount of one or more (e.g., one) other pharmaceutical
active ingredients (e.g., drugs).
[0029] This invention also provides methods for: (1) treating mild
cognitive impairment; (2) treating glaucoma; (3) treating cerebral
amyloid angiopathy; (4) treating stroke; (5) treating dementia; (6)
treating microgliosis; (7) treating brain inflammation; and (8)
treating olfactory function loss; wherein each method comprises
administering an effective amount of one or more (e.g., one)
compounds of formula (I) to a patient in need of such
treatment.
[0030] This invention also provides a kit comprising, in separate
containers, in a single package, pharmaceutical compositions for
use in combination, wherein one container comprises an effective
amount of a compound of formula (I) in a pharmaceutically
acceptable carrier, and another container (i.e., a second
container) comprises an effective amount of another
pharmaceutically active ingredient (as described below), the
combined quantities of the compound of formula (I) and the other
pharmaceutically active ingredient being effective to treat the
diseases or conditions mentioned in any of the above methods.
[0031] This invention also provides any of the above mentioned
methods, pharmaceutical compositions or kit wherein the compound of
formula (I) is selected from the group consisting of: compounds of
formulas IA, IB, IA.1, IB.1, 43A to 54A, 43 to 54, 85.1, 88.1, and
91.1.
[0032] This invention also provides any of the above mentioned
methods, pharmaceutical compositions or kit wherein the compound of
formula (I) is selected from the group consisting of: compounds 43A
to 54A, 43 to 54, 85.1, 88.1, and 91.1.
[0033] This invention also provides any of the above mentioned
methods, pharmaceutical compositions or kit wherein the compound of
formula (I) is selected from the group consisting of: compounds IA,
a IA.1, and IB.1.
[0034] This invention also provides any of the above mentioned
methods, pharmaceutical compositions or kit wherein the compound of
formula (I) is selected from the group consisting of: compounds 43A
to 54A.
[0035] This invention also provides any of the above mentioned
methods, pharmaceutical compositions or kit wherein the compound of
formula (I) is selected from the group consisting of: compounds 43
to 54.
[0036] This invention also provides any of the above mentioned
methods, pharmaceutical compositions or kit wherein the compound of
formula (I) is selected from the group consisting of: compounds
85.1, 88.1, 91.1, and 100 to 124.
[0037] This invention is also directed to any of the embodiments
described above wherein the compound of formula (I) is a compound
of formula (IA).
[0038] This invention is also directed to any of the embodiments
described above wherein the compound of formula (I) is a compound
of formula (IB).
DETAILED DESCRIPTION OF THE INVENTION
[0039] This invention provides novel compounds, that are gamma
secretase modulators, of the formula:
##STR00007##
selected from the group consisting of compounds:
##STR00008##
or a pharmaceutically acceptable salt, ester, or solvate thereof,
wherein:
[0040] G.sup.2, G.sup.3, G.sup.4, W, R.sup.1, Ring (A), Ring (E),
Ring (F), G.sup.5, G.sup.6, G.sup.7, R.sup.9, and R.sup.10 are
independently selected;
[0041] letters (A), (E) and (F) in the formulas are reference
fetters to identify the rings;
[0042] the dotted line between G.sup.1 and G.sup.2 represents an
optional bond;
[0043] the numbers (1), (2), (3), (4), and (5) are reference
numbers to identify positions of the Ring (A); G.sup.4 is at
position (1), G.sup.3 is at position (2), G.sup.2 is at position
(3), G.sup.1 is at position (4) and the N is at position (5);
[0044] when G.sup.5 is bound to G.sup.4 (formula IA) then G.sup.4
is a --C--, and when G.sup.5 is bound to G.sup.3 (formula IB) then
G.sup.3 is a --C--;
[0045] in said Ring (E): (a) G.sup.3 is C (i.e., G.sup.3 is
--C(R.sup.21).sub.q-- and q is 0), and G.sup.4 is C (i.e., G.sup.4
is --C(R.sup.21).sub.q-- and q is 0), or (b) G.sup.3 is N and
G.sup.4 is C and the double bond between G.sup.3 and G.sup.4 is
tautomerized to Ring (E),
[0046] in said Ring (F): (a) G.sup.3 is C (i.e., G.sup.3 is
--C(R.sup.21).sub.q-- and q is 0), and G.sup.4 is C (i.e., G.sup.4
is --C(R.sup.21).sub.q-- and q is 0), or (b) G.sup.4 is N and
G.sup.3 is C and the double bond between G.sup.3 and G.sup.4 is
tautomerized to Ring (F),
[0047] said Ring (E) or (F) is a 4 to 10 (and in one example 5 to
6) membered heteroaryl, aryl, cycioalkenyl, or heterocycloalkenyl
ring;
[0048] when said Ring (E) or (F) is a heterocycloalkenyl ring or a
heteroaryl ring, said Ring optionally comprises at least one (e.g.,
1 to 4, 1 to 3, or 1 to 2, or 1) other heteroatom selected from the
group consisting of: --NR.sup.2--, --O--, --S--, --S(O)--, and
--S(O).sub.2--;
[0049] said Ring (E) or (F) is optionally substituted with 1 to 6
independently selected R.sup.21 substituents;
[0050] d is 0 or 1 (and those skilled in the art will appreciate
that when d is 0 in the --N(R.sup.2).sub.d-moiety there is no
substituent on the N, thus, the moiety --N(R.sup.2).sub.d-- is
--N.dbd. or --NH-- when d is 0, i.e., when d is 0 in a moiety there
is the appropriate number of H atoms on the N to fill the required
valences);
[0051] m is 0 to 6;
[0052] n is 1 to 5;
[0053] p is 0 to 5;
[0054] q is 0, 1 or 2, and each q is independently selected (and
those skilled in the art will appreciate that when q is 0 in the
moiety --C(R.sup.21).sub.q this means that there is no R.sup.21
substituent on the carbon, and the --C(R.sup.21).sub.q moiety is
--CH.dbd. or --CH.sub.2--, i.e., when q is 0 in a moiety there is
the appropriate number of H atoms on the carbon to fill the
required valences);
[0055] r is 1 to 3;
[0056] t is 1 or 2;
[0057] W is selected from the group consisting of: --C(O)--,
--S(O).sub.2--, --S(O)--, and --C(.dbd.NR.sup.2)-- (and in one
example W is --C(O)--);
[0058] G.sup.1 is selected from the group consisting of: a direct
bond, --O--, --S--, --C(R.sup.21).sub.q--, --N(R.sup.2).sub.d--,
--C(O)--, S(O), S(O).sub.2, --C(N(R.sup.2).sub.2)-- (wherein each
R.sup.2 is independently selected), and --C(.dbd.NR.sup.2)--; and
with the provisos that: [0059] (1) when the optional bond between
G.sup.1 and G.sup.2 is absent (i.e., there is a single bond between
G.sup.1 and G.sup.2) then G.sup.1 is not --C(N(R.sup.2).sub.2)--;
and [0060] (2) when the optional bond between G.sup.1 and G.sup.2
is present (i.e., there is a double bond between G.sup.1 and
G.sup.2) then: [0061] (a) q for the --C(R.sup.21).sub.q group is 0
or 1 (and when q is 0 then there is a H on the carbon), and [0062]
(b) d for the --N(R.sup.2).sub.d-- group is 0 (and there is no H on
the N due to the double bond between G.sup.1 and G.sup.2 (i.e.,
between positions (3) and (4)); and [0063] (c) G.sup.1 is not a
direct bond, --O--, --S--, --C(O)--, --C(.dbd.NR.sup.2)--,
--S(O).sub.2--, or --S(O)--:
[0064] G.sup.2 is selected from the group consisting of: a direct
bond, --O--, --S--, --C(R.sup.21).sub.q, --N(R.sup.2).sub.d--,
--C(O)--, S(O), S(O).sub.2, --C(N(R.sup.2).sub.2)-- (wherein each
R.sup.2 is independently selected), and --C(.dbd.NR.sup.2)--; and
with the provisos that: [0065] (1) when the optional bond between
G.sup.1 and G.sup.2 is absent (i.e., there is a single bond between
G.sup.1 and G.sup.2) then G.sup.2 is not --C(N(R.sup.2).sub.2)--;
and [0066] (2) when the optional bond between G.sup.1 and G.sup.2
is present (i.e., there is a double bond between G.sup.1 and
G.sup.2), then: [0067] (a) q for the --C(R.sup.21).sub.q group is 0
or 1 (and when q is 0 then there is a H on the carbon), and [0068]
(b) d for the --N(R.sup.2).sub.d-- group is 0 (and there is no H on
the N due to the double bond between positions (3) and (4)); and
[0069] (c) G.sup.2 is not a direct bond, --O--, --S--, --C(O)--,
--C(.dbd.NR.sup.2)--)-, --S(O).sub.2--, or --S(O)--;
[0070] G.sup.5 is selected from the group consisting of: direct
bond, CH, --C(R.sup.21).sub.q, --N(R.sup.2).sub.d, --O--, --S--,
--S(O).sub.t; --C(O)--, --(C.dbd.NR.sup.2)--, --CHR.sup.3--,
C(R.sup.4).sub.2, --CF.sub.2--, --N(R.sup.2)--, --CR.sup.4(OH)--,
--CR.sup.4(OR.sup.4)--, cycloalkyl, and heteracycloalkyl;
[0071] G.sup.6 is selected from the group consisting of: C,
CR.sup.3, and N;
[0072] G.sup.7 is selected from the group consisting of: a direct
bond, --C(O)--, --(C.dbd.NR.sup.2)--, --CHR.sup.3--,
C(R.sup.4).sub.2, --CF.sub.2--, --N(R.sup.2)--, --O--, --S--,
--S(O).sub.t, --CR.sup.4(OH)--, --CR.sup.4(OR.sup.4)--,
--C.dbd.C--, alkynyl, --(CH.sub.2).sub.rN(R.sup.2)--,
--(CHR.sup.4).sub.rN(R.sup.2)--,
--(C(R.sup.4).sub.2).sub.rN(R.sup.2)--,
--N(R.sup.2)(CH.sub.2).sub.r--,
--N(R.sup.2)(CHR.sup.4).sub.r--N(R.sup.2)(C(R.sup.4).sub.2).sub.r--(CH.su-
b.2).sub.r--O--, --(CHR.sup.4).sub.r--O--,
--(C(R.sup.4).sub.2).sub.r--O--, --O--(CH.sub.2).sub.r--,
--O--(CHR.sup.4).sub.r--, --O--(C(R.sub.4).sub.2).sub.r--,
--C(O)NR.sup.5--, --O--C(O)--, --C(O)--O--, --O--C(O)--NR.sup.5--,
--NR.sup.5C(O)--, --(CH.sub.2).sub.rNR.sup.5--C(O)--,
--(CHR.sup.4).sub.rNR.sup.5--C(O)--,
--(C(R.sup.4).sub.2).sub.rNR.sup.5--C(O)--,
--C(O)NR.sup.5(CH.sub.2).sub.r--,
--C(O)NR.sup.5(CHR.sup.4).sub.r--,
--C(O)NR.sup.5(C(R.sup.4).sub.2).sub.r--, --NR.sup.5S(O).sub.t--,
--(CH.sub.2).sub.rNR.sup.5S(O).sub.t--,
--(CHR.sup.4).sub.rNR.sup.5S(O).sub.t--,
--(C(R.sup.4).sub.2).sub.rNR.sup.5S(O).sub.t--,
--S(O).sub.tNR.sup.5--, --S(O).sub.tNR.sup.5(CH.sub.2).sub.r--,
--S(O).sub.tNR.sup.5(CHR.sup.4).sub.r--,
--S(O).sub.tNR.sup.5(C(R.sup.4).sub.2).sub.r--,
--NR.sup.5--C(O)--O--, --NR.sup.5--C(O)--NR.sup.5--,
--NR.sup.5--S(O).sub.t--NR.sup.5--,
--NR.sup.5--C(.dbd.NR.sup.2)--NR.sup.5--,
--NR.sup.S--C(.dbd.NR.sup.2)--O--,
--O--C(.dbd.NR.sup.2)--NR.sup.5--, --O--N.dbd.C(R.sup.4)--,
--O--C(R.sup.4).dbd.N--, --N.dbd.C(R.sup.4)--O--,
--(CH.sub.2).sub.2--, --(C(R.sup.4).sub.2).sub.2--,
--(CHR.sup.4).sub.2--, --(CH.sub.2).sub.3--,
--(C(R.sup.4).sub.2).sub.3--, --(CHR.sup.4).sub.3--, cycloalkyl,
and heterocycloalkyl:
[0073] provided that 0 to 2 of the G.sup.1, G.sup.2, G.sup.3, and
G.sup.4 moieties are --N(R.sup.2).sub.d-- and each R.sup.2 is
independently selected and each d is independently selected, and
provided that Ring (A) does not have three consecutive ring
nitrogen atoms;
[0074] R.sup.1 is selected from the group consisting of: alkyl-,
alkenyl-, alkynyl-, aryl-, arylalkyl-, alkylaryl-, cycloalkyl-,
cycloalkenyl, cycloalkylalkyl-, fused benzocycloalkyl (i.e.,
benzofusedcycloalkyl), fused benzoheterocycloalkyl (i.e.,
benzofusedhetero-cycloalkyl), fused heteroarylcycloalkyl (i.e.,
heteroarylfusedcycloalkyl), fused heteroarylheterocycloalkyl (i.e.,
heteroarylfusedheterocycloalkyl), fused cycloalkylaryl (i.e.,
cycloalkyfusedlaryl), fused heterocycloalkylaryl (i.e.,
hetero-cycloalkylfusedaryl), fused cycloalkylheteroaryl (i.e.,
cycloalkylfusedheteroaryl), fused heterocycloalkylheteroaryl (i.e.,
heterocycloalkylfusedheteroaryl), fused benzocycloalkyl alkyl
(i.e., benzofusedcycloalkyl alkyl), fused benzoheterocycloalkyl
alkyl (i.e., benzofusedhetero-cycloalkyl alkyl), fused
heteroarylcycloalkyl alkyl (i.e., heteroarylfusedcycloalkyl alkyl),
fused heteroaryiheterocycloalkyl alkyl (i.e.,
heteroarylfusedheterocycloalkyl alkyl), fused cycloalkylaryl alkyl
(i.e., cycloalkyfusedlaryl alkyl), fused heterocycloalkylaryl alkyl
(i.e., hetero-cycloalkylfusedaryl alkyl), fused
cycloalkylheteroaryl alkyl (i.e., cycloalkylfusedheteroaryl alkyl),
fused heterocycloalkylheteroaryl alkyl (i.e.,
heterocycloalkylfusedheteroaryl alkyl), heteroaryl-,
heteroarylalkyl-, heterocyclyl-, heterocyclenyl, -and
heterocyclyalkyl-; wherein each of said alkyl-, alkenyl- and
alkynyl-, aryl-, arylalkyl-, alkylaryl-, cycloalkyl-,
cycloalkenyl-, cycloalkylalkyl-, fused benzocycloalkyl, fused
benzoheterocycloalkyl, fused heteroarylcycloalkyl, fused
heteroarylheterocycloalkyl, fused cycloalkylaryl, fused
heterocycloalkylaryl, fused cycloalkylheteroaryl, fused
heterocycloalkylheteroaryl, fused benzocycloalkyl alkyl, fused
benzoheterocycloalkyl alkyl, fused heteroarylcycloalkyl alkyl,
fused heteroarylheterocycloalkyl alkyl, fused cycloalkylaryl alkyl,
fused heterocycloalkylaryl alkyl, fused cycloalkylheteroaryl alkyl,
fused heterocycloalkylheteroaryl alkyl, heteroaryl-,
heteroarylalkyl-, heterocyclyl-, heterocyclenyl and
heterocyclyalkyl-R.sup.1 groups is optionally substituted with 1-5
independently selected R.sup.21 groups;
[0075] Each R.sup.2 is independently selected from the group
consisting of: H, --OH, --O-alkyl (i.e., alkoxy), --O-(halo
substituted alky) (such as, for example, --O-fluoroalkyl),
--NH(R.sup.4), --N(R.sup.4).sub.2 (wherein each R.sup.4 is
independently selected), --NH.sub.2, --S(O)R.sup.4,
--S(O)(OR.sup.4), --S(O).sub.2R.sup.4, --S(O).sub.2(OR.sup.4),
--S(O)NHR.sup.4, --S(O)N(R.sub.4).sub.2 (wherein each R.sup.4 is
independently selected), --S(O)NH.sub.2, --S(O).sub.2NHR.sup.4,
--S(O).sub.2N(R.sup.4).sub.2 (wherein each R.sup.4 is independently
selected), --S(O).sub.2NH.sub.2, --CN, --C(O).sub.2R.sup.4,
--C(O)NHR.sup.4, --C(O)N(R.sup.4).sub.2 (wherein each R.sup.4 is
independently selected), --C(O)NH.sub.2, --C(O)R.sup.4,
unsubstituted aryl, substituted aryl, unsubstituted heteroaryl,
substituted heteroaryl, unsubstituted substituted alkyl,
unsubstituted arylalkyl-, substituted arylalkyl-, unsubstituted
heteroarylalkyl-, substituted heteroarylalkyl-, unsubstituted
alkenyl, substituted alkenyl, unsubstituted alkynyl, substituted
alkynyl, unsubstituted cycloalkyl, and substituted cycloalkyl,
wherein said substituted aryl, heteroaryl, alkyl, arylalkyl-,
heteroarylalkyl-, alkenyl, alkynyl and cycloalkyl groups are
substituted with 1 to 5 independently selected R.sup.21 groups;
[0076] R.sup.3 is selected from the group consisting of: H, --OH,
halo, --O-alkyl (i.e., alkoxy), --O-(halo substituted alky) (such
as, for example, --O-fluoroalkyl), --NH(R.sup.4),
--N(R.sup.4).sub.2 (wherein each R.sup.4 is independently
selected), --NH.sub.2, --S(R.sup.4), --S(O)R.sup.4,
--S(O)(OR.sup.4), --S(O).sub.2R.sup.4, --S(O).sub.2(OR.sup.4),
--S(O)NHR.sup.4, --S(O)N(R.sup.4).sub.2 (wherein each R.sup.4 is
independently selected), --S(O)NH.sub.2, --S(O).sub.2NHR.sup.4,
--S(O).sub.2N(R.sup.4).sub.2 (wherein each R.sup.4 is independently
selected), --S(O).sub.2NH.sub.2, --CN, --C(O).sub.2R.sup.4,
--C(O)NHR.sup.4, --C(O)N(R.sup.4).sub.2 (wherein each R.sup.4 is
independently selected), --C(O)NH.sub.2, --C(O)R.sup.4,
unsubstituted aryl, substituted aryl, unsubstituted heteroaryl,
substituted heteroaryl, unsubstituted alkyl, substituted alkyl,
unsubstituted arylalkyl-, substituted arylalkyl-, unsubstituted
heteroarylalkyl-, substituted heteroarylalkyl-, unsubstituted
alkenyl, substituted alkenyl, unsubstituted alkynyl, substituted
alkynyl, unsubstituted cycloalkyl, and substituted cycloalkyl,
wherein said substituted aryl, heteroaryl, alkyl, arylalkyl-,
heteroarylalkyl-, alkenyl, alkynyl and cycloalkyl groups are
substituted with 1 to 5 independently selected R.sup.21 groups;
[0077] each R.sup.4 is independently selected from the group
consisting of: unsubstituted aryl, substituted aryl, unsubstituted
heteroaryl, substituted heteroaryl, unsubstituted alkyl,
substituted alkyl, unsubstituted arylalkyl-, substituted
arylalkyl-, unsubstituted heteroarylalkyl-, substituted
heteroarylalkyl-, unsubstituted alkenyl, substituted alkenyl,
unsubstituted alkynyl, substituted alkynyl, unsubstituted
cycloalkyl, and substituted cycloalkyl, wherein said substituted
aryl, heteroaryl, alkyl, arylalkyl-, heteroarylalkyl-, alkenyl,
alkynyl and cycloalkyl groups are substituted with 1 to 5
independently selected R.sup.21 groups;
[0078] each R.sup.5 is independently selected from the group
consisting of: H, unsubstituted alkyl, substituted alkyl,
unsubstituted alkenyl, substituted alkenyl, unsubstituted alkynyl,
substituted alkynyl, unsubstituted cycloalkyl, substituted
cycloalkyl, unsubstituted aryl, substituted aryl, unsubstituted
heteroaryl and substituted heteroaryl; wherein said substituted
groups are substituted with one or more (e.g., 1 to 5) substituents
independently selected from: R.sup.2;
[0079] Each R.sup.6 is independently selected from the group
consisting of: H, halo, --CF.sub.3, --O-alkyl (i.e., alkoxy),
--O-(halo substituted alky) (such as, for example,
--O-fluoroalkyl), --S(O)R.sup.4, --S(O)(OR.sup.4), --S(O)NHR.sup.4,
--S(O)N(R.sup.4).sub.2 (wherein each R.sup.4 is independently
selected), --S(O)NH.sub.2, --S(O).sub.2NHR.sup.4,
--S(O).sub.2N(R.sup.4).sub.2 (wherein each R.sup.4 is independently
selected), --S(O).sub.2NH.sub.2, --C(.dbd.NOR.sup.24)R.sup.25, and
--S(O).sub.2R.sup.24; --CN, --C(O).sub.2R.sup.4, --C(O)NHR.sup.4,
--C(O)N(R.sup.4).sub.2 (wherein each R.sup.4 is independently
selected), --C(O)NH.sub.2, --C(O)R.sup.4, unsubstituted aryl,
substituted aryl, unsubstituted heteroaryl, substituted heteroaryl,
unsubstituted alkyl, substituted alkyl, unsubstituted arylalkyl-,
substituted arylalkyl-, unsubstituted heteroarylalkyl-, substituted
heteroarylalkyl-, unsubstituted alkenyl, substituted alkenyl,
unsubstituted alkynyl, substituted alkynyl, unsubstituted
cycloalkyl, and substituted cycloalkyl, wherein said substituted
aryl, heteroaryl, arylalkyl-, heteroarylalkyl-, alkenyl, alkynyl
and cycloalkyl groups are substituted with 1 to 5 independently
selected R.sup.21 groups;
[0080] R.sup.9 is selected from the group consisting of:
arylalkoxy-, heteroarylalkoxy-, arylalkylamino-,
heteroarylalkylamino-, aryl-, arylalkyl-, cycloalkyl-,
cycloalkenyl, cycloalkylalkyl-, heteroaryl-, heteroarylalkyl-,
heterocyclyl-, heterocyclenyl-, and heterocyclyalkyl-, wherein each
of said R.sup.9 arylalkoxy-, heteroarylalkoxy-, arylalkylamino-,
heteroarylalkylamino-, aryl-, arylalkyl-, cycloalkyl-,
cycloalkenyl, cycloalkylalkyl-, heteroaryl-, heteroarylalkyl-,
heterocyclyl-, heterocyclenyl-, heterocyclyalkyl- and
heterocyclyalkyl- is optionally substituted with 1-5 independently
selected R.sup.21 groups;
[0081] R.sup.10 is selected from the group consisting of: aryl-
(e.g., phenyl), heteroaryl- (e.g., pyridyl), cycloalkyl-,
cycloalkenyl, cycloalkylalkyl-, heterocyclyl-, heterocyclenyl-,
heterocyclylalkyl-, heterocyclyalkenyl-, fused benzocycloalkyl-
(i.e., benzofusedcycloalkyl-), fused benzoheterocycloalkyl- (i.e.,
benzofusedheterocycloalkyl-), fused heteroarylcycloalkyl- (i.e.,
heteroarylfusedcycloalkyl-), fused heteroarylheterocycloalkyl-
(i.e., heteroarylfusedheterocycloalkyl-), fused cycloalkylaryl
(i.e., cycloalkyfusedlaryl-), fused heterocycloalkylaryl- (i.e.
heterocycloalkylfusedaryl-), fused cycloalkylheteroaryl- (i.e.,
cycloalkylfusedheteroaryl-), fused heterocycloalkylheteroaryl-
(i.e., heterocycloalkylfusedheteroaryl-),
##STR00009## ##STR00010##
wherein X is selected from the group consisting of: O,
--N(R.sup.14)-- and --S--; and wherein each of said R.sup.10
moieties is optionally substituted with 1-5 independently selected
R.sup.21 groups; or
[0082] R.sup.9 and R.sup.10 are linked together to form a fused
tricyclic ring system wherein R.sup.9 and R.sup.10 are as defined
above and the ring linking R.sup.9 and R.sup.10 is an alkyl ring,
or a heteroalkyl ring, or an aryl ring, or a heteroaryl ring, or an
alkenyl ring, or a heteroalkenyl ring (for example, the tricyclic
ring system is formed by linking the atoms adjacent to the atoms by
which R.sup.9 and R.sup.10 are bound together);
[0083] R.sup.14 is selected from the group consisting of H, alkyl,
alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl,
heterocyclyl, heterocyclenyl, heterocyclylalkyl,
heterocyclyalkenyl-, aryl, arylalkyl, heteroaryl, heteroarylalkyl,
--CN, --C(O)R.sup.15, --C(O)OR.sup.15, --C(O)N(R.sup.15)(R.sup.16),
--S(O)N(R.sup.15)(R.sup.16), --S(O).sub.2N(R.sup.15)(R.sup.16),
--C(.dbd.NOR.sup.15)R.sup.16, and --P(O)(OR.sup.15)(OR.sup.16);
[0084] R.sup.15A and R.sup.16A are independently selected from the
group consisting of alkyl, alkenyl, alkynyl, cycloalkyl,
cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl,
heteroaryl, heteroarylalkyl, arylcycloalkyl, arylheterocyclyl,
(R.sup.18).sub.n-alkyl, (R.sup.18).sub.n-cycloalkyl,
(R.sup.18).sub.n-cycloalkylalkyl, (R.sup.18).sub.n-heterocyclyl,
(R.sup.18).sub.n-heterocyclylalkyl, (R.sup.18).sub.n-aryl,
(R.sup.18).sub.n-arylalkyl, (R.sup.18).sub.n-heteroaryl and
(R.sup.18).sub.n-heteroarylalkyl; or
[0085] R.sup.15, R.sup.16 and R.sup.17 are independently selected
from the group consisting of H, alkyl, alkenyl, alkynyl,
cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl,
arylalkyl, heteroaryl, heteroarylalkyl, arylcycloalkyl,
arylheterocyclyl, (R.sup.18).sub.n-alkyl,
(R.sup.18).sub.n-cycloalkyl, (R.sup.18).sub.n-cycloalkylalkyl,
(R.sup.18).sub.n-heterocyclyl, (R.sup.18).sub.n-heterocyclylalkyl,
(R.sup.18).sub.n-aryl, (R.sup.18).sub.n-arylalkyl,
(R.sup.18).sub.n-heteroaryl and
(R.sup.18).sub.n-heteroarylalkyl;
[0086] each R.sup.18 is independently selected from the group
consisting of alkyl, alkenyl, alkynyl, aryl, arylalkyl,
arylalkenyl, arylalkynyl, --NO.sub.2, halo, heteroaryl,
HO-alkyoxyalkyl, --CF.sub.3, --ON, alkyl-CN, --C(O)R.sup.19,
--C(O)OH, --C(O)OR.sup.19, --C(O)NHR.sup.20, --C(O)NH.sub.2,
--C(O)NH.sub.2--C(O)N(alkyl).sub.2, --C(O)N(alkyl)(aryl),
--C(O)N(alkyl)(heteroaryl), --SR.sup.19,
--S(O).sub.2R.sup.20--S(O)NH(alkyl), --S(O)N(alkyl)(alkyl),
--S(O)NH(aryl), --S(O).sub.2NH.sub.2, --S(O).sub.2NHR.sup.19,
--S(O).sub.2NH(heterocyclyl), --S(O).sub.2N(alkyl).sub.2,
--S(O).sub.2N(alkyl)(aryl), --OCF.sub.3, --OH, --OR.sup.20,
--O-heterocyclyl, --O-cycloalkylalkyl, --O-heterocyclylalkyl,
--NH.sub.2, --NHR.sup.20, --N(alkyl).sub.2, --N(arylalkyl).sub.2,
--N(arylalkyl)-(heteroarylalkyl), --NHC(O)R.sup.20,
--NHC(O)NH.sub.2, --NHC(O)NH(alkyl), --NHC(O)N(alkyl)(alkyl),
--N(alkyl)C(O)NH(alkyl), --N(alkyl)C(O)N(alkyl)(alkyl),
--NHS(O).sub.2R.sup.20, --NHS(O).sub.2NH(alkyl),
--NHS(O).sub.2N(alkyl)(alkyl), --N(alkyl)S(O).sub.2NH(alkyl) and
--N(alkyl)S(O).sub.2N(alkyl)(alkyl); or
[0087] two R.sup.18 moieties on adjacent carbons can be linked
together to form a
##STR00011##
[0088] R.sup.19 is selected from the group consisting of: alkyl,
cycloalkyl, aryl, arylalkyl and heteroarylalkyl;
[0089] R.sup.20 is selected from the group consisting of: alkyl,
cycloalkyl, aryl, halo substituted aryl, arylalkyl, heteroaryl and
heteroarylalkyl;
[0090] each R.sup.21 is independently selected from the group
consisting of: alkyl, alkenyl, alkynyl, cycloalkyl,
cycloalkylalkyl, cycloalkenyl, heterocycloalkyl,
heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl,
heteroarylalkyl, halo, --ON, --OR.sup.15, --C(O)R.sup.15,
--C(O)OR.sup.15, --C(O)N(R.sup.15)(R.sup.16), --SR.sup.15,
--P(O)(CH.sub.3).sub.2, --SO(.dbd.NR.sup.15)R.sup.16--, --SF.sub.5,
--OSF.sub.5, --Si(R.sup.15A).sub.3 wherein each R.sup.15A is
independently selected --S(O)N(R.sup.15)(R.sup.16),
--CH(R.sup.15)(R.sup.16), --S(O).sub.2N(R.sup.15)(R.sup.16),
--C(.dbd.NOR.sup.15)R.sup.16, --P(O)(OR.sup.15)(OR.sup.16),
--N(R.sup.15)(R.sup.16), -alkyl-N(R.sup.15)(R.sup.16),
--N(R.sup.15)C(O)R.sup.16, --CH.sub.2--N(R.sup.15)C(O)R.sup.16,
--CH.sub.2--N(R.sup.15)C(O)N(R.sup.16)(R.sup.17),
--CH.sub.2--R.sup.15; --CH.sub.2N(R.sup.15)(R.sup.16),
--N(R.sup.15)S(O)R.sup.16A, --N(R.sup.15)S(O).sub.2R.sup.16A,
--CH.sub.2--N(R.sup.15)S(O).sub.2R.sup.16A,
--N(R.sup.15)S(O).sub.2N(R.sup.16)(R.sup.17),
--N(R.sup.15)S(O)N(R.sup.16)(R.sup.17),
--N(R.sup.15)C(O)N(R.sup.16)(R.sup.17),
--CH.sub.2--N(R.sup.15)C(O)N(R.sup.16)(R.sup.17),
--N(R.sup.15)C(O)OR.sup.16, --CH.sub.2--N(R.sup.15)C(O)OR.sup.16,
--S(O)R.sup.15A, .dbd.NOR.sup.15, --N.sub.3, --NO.sub.2,
--S(O).sub.2R.sup.15A, --O--N.dbd.C(R.sup.4).sub.2 (wherein each
R.sup.4 is independently selected), and --O--N.dbd.C(R.sup.4).sub.2
wherein R.sup.4 is taken together with the carbon atom to which
they are bound to form a 5 to 10 membered ring, said ring
optionally containing 1 to 3 heteroatoms selected from the group
consisting of --O--, --S--, --S(O)--, --S(O).sub.2--, and
--NR.sup.2--; wherein each of said alkyl, alkenyl, alkynyl,
cycloalkyl, cycloalkylalkyl, cycloalkenyl, heterocycloalkyl,
heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, and
heteroarylalkyl R.sup.21 groups is optionally substituted with 1 to
5 independently selected R.sup.22 groups;
[0091] each R.sup.22 group is independently selected from the group
consisting of alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl,
aryl, heteroaryl, halo, --CF.sub.3, --CN, --OR.sup.15,
--C(O)R.sup.15, --C(O)OR.sup.15, -alkyl-C(O)OR.sup.15,
C(O)N(R.sup.15)(R.sup.16), --SR.sup.15,
--S(O)N(R.sup.15)(R.sup.16), --S(O).sub.2N(R.sup.15)(R.sup.16),
--C(.dbd.NOR.sup.15)R.sup.16, --P(O)(OR.sup.15)(OR.sup.16),
--N(R.sup.15)(R.sup.16), -alkyl-N(R.sup.15)(R.sup.16),
--N(R.sup.15)C(O)R.sup.16, --CH.sub.2--N(R.sup.15)C(O)R.sup.16,
--N(R.sup.15)S(O)R.sup.16A, --N(R.sup.15)S(O).sub.2R.sup.16A,
--CH.sub.2--N(R.sup.15)S(O).sub.2R.sup.16A,
--N(R.sup.15)S(O).sub.2N(R.sup.16)(R.sup.17),
--N(R.sup.15)S(O)N(R.sup.16)(R.sup.17),
--N(R.sup.15)C(O)N(R.sup.16)(R.sup.17),
--CH.sub.2--N(R.sup.15)C(O)N(R.sup.16)(R.sup.17),
--N(R.sup.15)C(O)OR.sup.16, --CH.sub.2--N(R.sup.15)C(O)OR.sup.16,
--N.sub.3, .dbd.NOR.sup.15, --NO.sub.2, --S(O)R.sup.15A and
--S(O).sub.2R.sup.15A; and
[0092] provided that: [0093] Ring (A) does not have any --S--S--,
--S--S(O)--, --S--S(O).sub.2--, --S(O)--S(O)--,
--S(O)--S(O).sub.2--, or --S(O).sub.2--S(O).sub.2-- bonds in the
ring; [0094] Ring (A) does not have any --O--O-- bonds in the ring;
[0095] Ring (A) does not have any --O--S--, --O--S(O)--, or
--O--S(O).sub.2-- bonds in the ring; [0096] Ring (A) does not have
any --N--S--N-- bonds in the ring; [0097] Ring (A) does not have
any --N--O--N-- bonds in the ring; and [0098] Ring (A) does not
have three adjacent nitrogent atoms in the ring.
[0099] The compounds of this invention are useful for treating
central nervous system disorders such as, for example,
neurodegenerative diseases such as Alzheimer's disease and other
diseases relating to the deposition of amyloid protein. They are
especially useful for reducing Amyloid beta (hereinafter referred
to as A.beta.) production which is effective in the treatment of
diseases caused by A.beta. such as, for example, Alzheimers and
Down Syndrome.
[0100] Thus, for example, the compounds of this invention can be
used to treat the following diseases or conditions: Alzheimers
disease, mild cognitive impairment (MCI), Downs Syndrome, Glaucoma
(Guo et. al., Proc. Natl. Acad. Sci. USA 104, 13444-13449 (2007)),
Cerebral amyloid angiopathy, stroke or dementia (Frangione et al.,
Amyloid: J. Protein folding Disord. 8, suppl. 1, 36-42 (2001),
Microgliosis and brain inflammation (M P Lamber, Proc. Natl. Acad.
Sci, USA 95, 6448-53 (1998)), and Olfactory function loss
(Getchell, et. al. Neurobiology of Aging, 663-673, 24, 2003).
[0101] In one embodiment of the invention, R.sup.1 is selected from
the group consisting of: alkyl-, alkenyl-, alkynyl-, aryl-,
arylalkyl-, alkylaryl-, cycloalkyl-, cycloalkenyl,
cycloalkylalkyl-, fused benzocycloalkyl (i.e.,
benzofusedcycloalkyl), fused benzoheterocycloalkyl (i.e.,
benzofusedhetero-cycloalkyl), fused heteroarylcycloalkyl (i.e.,
heteroarylfusedcycloalkyl), fused heteroaryiheterocycloalkyl (i.e.,
heteroarylfusedheterocycloalkyl), heteroaryl-, heteroarylalkyl-,
heterocyclyl-, heterocyclenyl, -and heterocyclyalkyl-; and wherein
each of said alkyl-, alkenyl- and alkynyl-, aryl-, arylalkyl-,
alkylaryl-, cycloalkyl-, cycloalkenyl-, cycloalkylalkyl-, fused
benzocycloalkyl, fused benzoheterocycloalkyl, fused
heteroarylcycloalkyl, fused heteroarylheterocycloalkyl,
heteroaryl-, heteroarylalkyl-, heterocyclyl-, heterocyclenyl and
heterocyclyalkyl-R.sup.1 groups is optionally substituted with 1-5
independently selected R.sup.21 groups.
[0102] Examples of moieties formed when R.sup.10 and R.sup.9 are
linked together to form a fused tricyclic ring system include, but
are not limited to:
##STR00012##
wherein R.sup.10 and R.sup.9 are as defined for formula (I), and
Ring C is the ring linking R.sup.10 and R.sup.9, that is Ring C is
an alkyl ring, or a heteroalkyl ring, or an aryl ring, or a
heteroaryl ring, or an alkenyl ring, or a heteroalkenyl ring.
[0103] Examples of moieties formed when R.sup.10 and R.sup.9 are
linked together to form a fused tricyclic ring system include, but
are not limited to:
##STR00013##
wherein R.sup.10 and R.sup.9 are as defined for formula (I), and
Ring C is the ring linking R.sup.10 and R.sup.9, that is Ring C is
a heteroalkyl ring, or a heteroaryl ring, or a heteroalkenyl
ring.
[0104] In one example, the fused tricyclic ring system formed when
R.sup.10 and R.sup.9 are linked together is
##STR00014##
wherein Ring C is a heteroalkyl ring, or a heteroaryl ring, or a
heteroalkenyl ring, thus, for example, the tricyclic ring system is
formed by linking the atoms adjacent to the atoms by which R.sup.10
and R.sup.9 are bound together), and wherein said fused tricyclic
ring system is optionally substituted with 1 to 5 independently
selected R.sup.21 groups.
[0105] Other examples of moieties formed when R.sup.10 and R.sup.9
are linked together to form a fused tricyclic ring system include,
but are not limited to:
##STR00015##
[0106] Another embodiment of this is directed to compounds of
formula (I) wherein at least one (e.g., 1 to 3, or 1-2, or 1) group
selected from the group consisting of: --SF.sub.5, --OSF.sub.5, and
--Si(R.sup.15A).sub.3 is present, and wherein each R.sup.15A is
independently selected, and wherein when there is more than one
group, each group is independently selected.
[0107] Another embodiment of this is directed to compounds of
formula (I) wherein at least one (e.g., 1 to 3, or 1-2, or 1) group
selected from the group consisting of: --SF.sub.5 and --OSF.sub.5
is present, and wherein when there is more than one group, each
group is independently selected.
[0108] In one embodiment of this invention one group selected from
the group consisting of: --SF.sub.5, --OSF.sub.5, and
--Si(R.sup.15A).sub.3 (wherein each R.sup.15A is independently
selected) is present in the compounds of formula (I).
[0109] In another embodiment of this invention two groups selected
from the group consisting of: --SF.sub.5, --OSF.sub.5, and
--Si(R.sup.15A).sub.3 (wherein each R.sup.15A is independently
selected) are present in the compounds of formula (I).
[0110] In another embodiment of this invention three groups
selected from the group consisting of: --SF.sub.5, --OSF.sub.5, and
--Si(R.sup.15A).sub.3 (wherein each R.sup.15A is independently
selected) are present in the compounds of formula (I).
[0111] In another embodiment of this invention two groups selected
from the group consisting of: --SF.sub.5, --OSF.sub.5, and
--Si(R.sup.15A).sub.3 (wherein each R.sup.15A is independently
selected) are present in the compounds of formula (I), wherein at
least one group is other than --Si(R.sup.15A).sub.3.
[0112] In another embodiment of this invention three groups
selected from the group consisting of: --SF.sub.5, --OSF.sub.5, and
--Si(R.sup.15A).sub.3 (wherein each R.sup.15A is independently
selected) are present in the compounds of formula (I), wherein at
least one group is other than --Si(R.sup.15A).sub.3.
[0113] In another embodiment of this invention one group selected
from the group consisting of: --SF.sub.5, --OSF.sub.5, and
--Si(R.sup.15A).sub.3 (wherein each R.sup.15A is independently
selected from the group consisting of alkyl (e.g., methyl and
ethyl) and aryl (e.g., phenyl)) is present in the compounds of
formula (I).
[0114] In another embodiment of this invention two groups selected
from the group consisting of: --SF.sub.5, --OSF.sub.5, and
--Si(R.sup.15A).sub.3 (wherein each R.sup.15A is independently
selected from the group consisting of alkyl (e.g., methyl and
ethyl) and aryl (e.g., phenyl)) are present in the compounds of
formula (I).
[0115] In another embodiment of this invention three groups
selected from the group consisting of: --SF.sub.5, --OSF.sub.5, and
--Si(R.sup.15A).sub.3 (wherein each R.sup.15A is independently
selected from the group consisting of alkyl (e.g., methyl and
ethyl) and aryl (e.g., phenyl)) are present in the compounds of
formula (I).
[0116] In another embodiment of this invention two groups selected
from the group consisting of: --SF.sub.5, --OSF.sub.5, and
--Si(R.sup.15A).sub.3 (wherein each R.sup.15A is independently
selected from the group consisting of alkyl (e.g., methyl and
ethyl) and aryl (e.g., phenyl)) are present in the compounds of
formula (I), wherein at least one group is other than
--Si(R.sup.15A).sub.3.
[0117] In another embodiment of this invention three groups
selected from the group consisting of: --SF.sub.5, --OSF.sub.5, and
--Si(R.sup.15A).sub.3 (wherein each R.sup.15A is independently
selected from the group consisting of alkyl (e.g., methyl and
ethyl) and aryl (e.g., phenyl)) are present in the compounds of
formula (I), wherein at least one group is other than
--Si(R.sup.15A).sub.3.
[0118] In another embodiment of this invention one group selected
from the group consisting of: --SF.sub.5, --OSF.sub.5, and
--Si(R.sup.15A).sub.3 (wherein each R.sup.15A is independently
selected from the group consisting of methyl, ethyl and phenyl) is
present in the compounds of formula (I).
[0119] In another embodiment of this invention two groups selected
from the group consisting of: --SF.sub.5, --OSF.sub.5, and
--Si(R.sup.15A).sub.3 (wherein each R.sup.15A is independently
selected from the group consisting of methyl, ethyl and phenyl) are
present in the compounds of formula (I).
[0120] In another embodiment of this invention three groups
selected from the group consisting of: --SF.sub.5, --OSF.sub.5, and
--Si(R.sup.15A).sub.3 (wherein each R.sup.15A is independently
selected from the group consisting of methyl, ethyl and phenyl) are
present in the compounds of formula (I).
[0121] In another embodiment of this invention two groups selected
from the group consisting of: --SF.sub.5, --OSF.sub.5, and
--Si(R.sup.15A).sub.3 (wherein each R.sup.15A is independently
selected from the group consisting of methyl, ethyl and phenyl) are
present in the compounds of formula (I), wherein at least one group
is other than --Si(R.sup.15A).sub.3.
[0122] In another embodiment of this invention three groups
selected from the group consisting of: --SF.sub.5, --OSF.sub.5, and
--Si(R.sup.15A).sub.3 (wherein each R.sup.15A is independently
selected from the group consisting of methyl, ethyl and phenyl) are
present in the compounds of formula (I), wherein at least one group
is other than --Si(R.sup.15A).sub.3.
[0123] In another embodiment of this invention one group selected
from the group consisting of: --SF.sub.5, --OSF.sub.5, and
--Si(R.sup.15A).sub.3 (wherein each R.sup.15A is independently
selected from the group consisting of methyl and ethyl) is present
in the compounds of formula (I).
[0124] In another embodiment of this invention two groups selected
from the group consisting of: --SF.sub.5, --OSF.sub.5, and
--Si(R.sup.15A).sub.3 (wherein each R.sup.15A is independently
selected from the group consisting of methyl and ethyl) are present
in the compounds of formula (I).
[0125] In another embodiment of this invention three groups
selected from the group consisting of: --SF.sub.5, --OSF.sub.5, and
--Si(R.sup.15A).sub.3 (wherein each R.sup.15A is independently
selected from the group consisting of methyl and ethyl) are present
in the compounds of formula (I).
[0126] In another embodiment of this invention two groups selected
from the group consisting of: --SF.sub.5, --OSF.sub.5, and
--Si(R.sup.15A).sub.3 (wherein each R.sup.15A is independently
selected from the group consisting of methyl and ethyl) are present
in the compounds of formula (I), wherein at least one group is
other than --Si(R.sup.15A).sub.3.
[0127] In another embodiment of this invention three groups
selected from the group consisting of: --SF.sub.5, --OSF.sub.5, and
--Si(R.sup.15A).sub.3 (wherein each R.sup.15A is independently
selected from the group consisting of methyl and ethyl) are present
in the compounds of formula (I), wherein at least one group is
other than --Si(R.sup.15A).sub.3.
[0128] In another embodiment of this invention one group selected
from the group consisting of: --SF.sub.5, --OSF.sub.5, and
--Si(R.sup.15A).sub.3 is present in the compounds of formula (I),
and said --Si(R.sup.15A).sub.3 group is selected from the group
consisting of: --Si(CH.sub.3).sub.3, --Si(CH.sub.3).sub.2-phenyl,
and --Si(CH.sub.2CH.sub.3).sub.2CH.sub.3.
[0129] In another embodiment of this invention two groups selected
from the group consisting of: --SF.sub.5, --OSF.sub.5, and
--Si(R.sup.15A).sub.3 are present in the compounds of formula (I),
and said --Si(R.sup.15A).sub.3 group is selected from the group
consisting of: --Si(CH.sub.3).sub.3, --Si(CH.sub.3).sub.2-phenyl,
and --Si(CH.sub.2CH.sub.3).sub.2CH.sub.3.
[0130] In another embodiment of this invention three groups
selected from the group consisting of: --SF.sub.5, --OSF.sub.5, and
--Si(R.sup.15A).sub.3 are present in the compounds of formula (I),
and said --Si(R.sup.15A).sub.3 group is selected from the group
consisting of: --Si(CH.sub.3).sub.3, --Si(CH.sub.3).sub.2-phenyl,
and --Si(CH.sub.2CH.sub.3).sub.2CH.sub.1
[0131] In another embodiment of this invention two groups selected
from the group consisting of: --SF.sub.5, --OSF.sub.5, and
--Si(R.sup.15A).sub.3 are present in the compounds of formula (I),
wherein at least one group is other than --Si(R.sup.15A).sub.3, and
said --Si(R.sup.15A).sub.3 group is selected from the group
consisting of: --Si(CH.sub.3).sub.3, --Si(CH.sub.3).sub.2-phenyl,
and --Si(CH.sub.2CH.sub.3).sub.2CH.sub.3.
[0132] In another embodiment of this invention three groups
selected from the group consisting of: --SF.sub.5, --OSF.sub.5, and
--Si(R.sup.15A).sub.3 are present in the compounds of formula (I),
wherein at least one group is other than --Si(R.sup.15A).sub.3, and
said --Si(R.sup.15A).sub.3 group is selected from the group
consisting of: --Si(CH.sub.3).sub.3, --Si(CH.sub.3).sub.2-phenyl,
and --Si(CH.sub.2CH.sub.3).sub.2CH.sub.3.
[0133] In another embodiment of this invention one group selected
from the group consisting of: --SF.sub.5, --OSF.sub.5, and
--Si(R.sup.15A).sub.3 is present in the compounds of formula (I),
and said --Si(R.sup.15A).sub.3 group is selected from the group
consisting of: --Si(CH.sub.3).sub.3 and
--Si(CH.sub.2CH.sub.3).sub.2CH.sub.3
[0134] In another embodiment of this invention two groups selected
from the group consisting of: --SF.sub.5, --OSF.sub.5, and
--Si(R.sup.15A).sub.3 are present in the compounds of formula (I),
and said --Si(R.sup.15A).sub.3 group is selected from the group
consisting of: --Si(CH.sub.3).sub.3 and
--Si(CH.sub.2CH.sub.3).sub.2CH.sub.3.
[0135] In another embodiment of this invention three groups
selected from the group consisting of: --SF.sub.5, --OSF.sub.5, and
--Si(R.sup.15A).sub.3 are present in the compounds of formula (I)
and said --Si(R.sup.15A).sub.3 group is selected from the group
consisting of: --Si(CH.sub.3).sub.3 and
--Si(CH.sub.2CH.sub.3).sub.2CH.sub.3.
[0136] In another embodiment of this invention two groups selected
from the group consisting of: --SF.sub.5, --OSF.sub.5, and
--Si(R.sup.15A).sub.3 are present in the compounds of formula (I),
wherein at least one group is other than --Si(R.sup.15A).sub.3, and
said --Si(R.sup.15A).sub.3 group is selected from the group
consisting of: --Si(CH.sub.3).sub.3 and
--Si(CH.sub.2CH.sub.3).sub.2CH.sub.3.
[0137] In another embodiment of this invention three groups
selected from the group consisting of: --SF.sub.5, --OSF.sub.5, and
--Si(R.sup.15A).sub.3 are present in the compounds of formula (I),
wherein at least one group is other than --Si(R.sup.15A).sub.3, and
said --Si(R.sup.15A).sub.3 group is selected from the group
consisting of: --Si(CH.sub.3).sub.3, --Si(CH.sub.3).sub.2-phenyl,
and --Si(CH.sub.2CH.sub.3).sub.2CH.sub.3.
[0138] In another embodiment of this invention one group selected
from the group consisting of: --SF.sub.5, --OSF.sub.5, and
--Si(CH.sub.3).sub.3 is present.
[0139] In another embodiment of this invention two groups selected
from the group consisting of: --SF.sub.5, --OSF.sub.5, and
--Si(CH.sub.3).sub.3 are present in the compounds of formula
(I).
[0140] In another embodiment of this invention three groups
selected from the group consisting of: --SF.sub.5, --OSF.sub.5, and
--Si(CH.sub.3).sub.3 are present in the compounds of formula
(I).
[0141] In another embodiment of this invention two groups selected
from the group consisting of: --SF.sub.5, --OSF.sub.5, and
--Si(CH.sub.3).sub.3 are present in the compounds of formula (I),
wherein at least one group is other than --Si(CH.sub.3).sub.3.
[0142] In another embodiment of this invention three groups
selected from the group consisting of: --SF.sub.5, --OSF.sub.5, and
--Si(R.sup.24).sub.3 are present in the compounds of formula (I),
wherein at least one group is other than --Si(CH.sub.3).sub.3
[0143] In another embodiment of this invention one group selected
from the group consisting of: --SF.sub.5 and --OSF.sub.5 is present
in the compounds of formula (I).
[0144] In another embodiment of this invention two groups selected
from the group consisting of: --SF.sub.5 and --OSF.sub.5 are
present in the compounds of formula (I).
[0145] In another embodiment of this invention three groups
selected from the group consisting of: --SF.sub.5 and --OSF.sub.5
are present in the compounds of formula (I)
[0146] In another embodiment of this invention one --SF.sub.5 group
is present in the compounds of formula (I).
[0147] In another embodiment of this invention two --SF.sub.5
groups are present in the compounds of formula (I).
[0148] In another embodiment of this invention three --SF.sub.5
groups are present in the compounds of formula (I).
[0149] In another embodiment of this invention one --OSF.sub.5
group is present in the compounds of formula (I).
[0150] In another embodiment of this invention two --OSF.sub.5
groups are present in the compounds of formula (I).
[0151] In another embodiment of his invention three --OSF.sub.5
groups are present in the compounds of formula (I).
[0152] In another embodiment of this invention one
--Si(R.sup.15a).sub.3 (wherein each R.sup.15A is independently
selected) group is present in the compounds of formula (I).
[0153] In another embodiment of this invention two
--Si(R.sup.15A).sub.3 (wherein each R.sup.15A is independently
selected) groups are present in the compounds of formula (I).
[0154] In another embodiment of this invention three
--Si(R.sup.15A).sub.3 (wherein each R.sup.15A is independently
selected) groups are present in the compounds of formula (I).
[0155] In another embodiment of this invention one
--Si(R.sup.15A).sub.3 (wherein each R.sup.15A is independently
selected from the group consisting of alkyl (e.g., methyl and
ethyl) and aryl (e.g., phenyl)) is present in the compounds of
formula (I).
[0156] In another embodiment of this invention two
--Si(R.sup.15A).sub.3 (wherein each R.sup.15A is independently
selected from the group consisting of alkyl (e.g., methyl and
ethyl) and aryl (e.g., phenyl)) is present in the compounds of
formula (I).
[0157] In another embodiment of this invention three
--Si(R.sup.15A).sub.3 (wherein each R.sup.15A is independently
selected from the group consisting of alkyl (e.g., methyl and
ethyl) and aryl (e.g., phenyl)) is present in the compounds of
formula (I).
[0158] In another embodiment of this invention one
--Si(R.sup.15A).sub.3 (wherein each R.sup.15A is independently
selected from the group consisting of methyl, ethyl and phenyl) is
present in the compounds of formula (I).
[0159] In another embodiment of this invention two
--Si(R.sup.15A).sub.3 (wherein each R.sup.15A is independently
selected from the group consisting of methyl, ethyl and phenyl) is
present in the compounds of formula (I).
[0160] In another embodiment of this invention three
--Si(R.sup.15A).sub.3 (wherein each R.sup.15A is independently
selected from the group consisting of methyl, ethyl and phenyl) is
present in the compounds of formula (I).
[0161] In another embodiment of this invention one
--Si(R.sup.15A).sub.3 (wherein each R.sup.15A is independently
selected from the group consisting of methyl and ethyl) is present
in the compounds of formula (I).
[0162] In another embodiment of this invention two
--Si(R.sup.15A).sub.3 (wherein each R.sup.15A is independently
selected from the group consisting of methyl and ethyl) is present
in the compounds of formula (I).
[0163] In another embodiment of this invention three
--Si(R.sup.15A).sub.3 (wherein each R.sup.15A is independently
selected from the group consisting of methyl and ethyl) is present
in the compounds of formula (I).
[0164] In another embodiment of this invention one
--Si(R.sup.15A).sub.3 group is present in the compounds of formula
(I), and said --Si(R.sup.15A).sub.3 group is selected from the
group consisting of: --Si(CH.sub.3).sub.3,
--Si(CH.sub.3).sub.2-phenyl, and
--Si(CH.sub.2CH.sub.3).sub.2CH.sub.3.
[0165] In another embodiment of this invention two
--Si(R.sup.15A).sub.3 groups are present in the compounds of
formula (I), and said --Si(R.sup.15A).sub.3 groups are
independently selected from the group consisting of:
--Si(CH.sub.3).sub.3, --Si(CH.sub.3).sub.2-phenyl, and
--Si(CH.sub.2CH.sub.3).sub.2CH.sub.3.
[0166] In another embodiment of this invention three
--Si(R.sup.15A).sub.3 groups are present in the compounds of
formula (I), and said --Si(R.sup.15A).sub.3 groups are
independently selected from the group consisting of:
--Si(CH.sub.3).sub.3, --Si(CH.sub.3).sub.2-phenyl, and
--Si(CH.sub.2CH.sub.3).sub.2CH.sub.3.
[0167] In another embodiment of this invention one
--Si(R.sup.15A).sub.3 group is present in the compounds of formula
(I), and said --Si(R.sup.15A).sub.3 group is selected from the
group consisting of: --Si(CH.sub.3).sub.3 and
--Si(CH.sub.2CH.sub.3).sub.2CH.sub.3.
[0168] In another embodiment of this invention two
--Si(R.sup.15A).sub.3 groups are present in the compounds of
formula (I), and said --Si(R.sup.15A).sub.3 groups are
independently selected from the group consisting of:
--Si(CH.sub.3).sub.3 and --Si(CH.sub.2CH.sub.3).sub.2CH.sub.3.
[0169] In another embodiment of this invention three
--Si(R.sup.15A).sub.3 groups are present in the compounds of
formula (I), and said --Si(R.sup.15A).sub.3 groups are
independently selected from the group consisting of:
--Si(CH.sub.3).sub.3 and --Si(CH.sub.2CH.sub.3).sub.2CH.sub.3.
[0170] In another embodiment of this invention one
--Si(R.sup.15A).sub.3 group is present in the compounds of formula
(I), and said --Si(R.sup.15A).sub.3 group is
--Si(CH.sub.3).sub.3.
[0171] In another embodiment of this invention two
--Si(R.sup.15A).sub.3 groups are present in the compounds of
formula (I), and said --Si(R.sup.15A).sub.3 groups are
--Si(CH.sub.3).sub.3.
[0172] In another embodiment of this invention three
--Si(R.sup.15A).sub.3 groups are present in the compounds of
formula (I), and said --Si(R.sup.15A).sub.3 groups are
--Si(CH.sub.3).sub.3.
[0173] In another embodiment of this invention one group selected
from the group consisting of: --SF.sub.5, --OSF.sub.5,
--Si(CH.sub.3).sub.3, --Si(CH.sub.3).sub.2-phenyl, and
--Si(CH.sub.2CH.sub.3).sub.2CH.sub.3) is present in the compounds
of formula (I),
[0174] In another embodiment of this invention one group selected
from the group consisting of: --SF.sub.5, --OSF.sub.5,
--Si(CH.sub.3).sub.3, and --Si(CH.sub.2CH.sub.3).sub.2CH.sub.3) is
present in the compounds of formula (I).
[0175] In another embodiment of this invention one group selected
from the group consisting of: --SF.sub.5, --OSF.sub.5, and
--Si(CH.sub.3).sub.3, is present in the compounds of formula
(I).
[0176] In another embodiment of this invention one --SF.sub.5 group
is present in the compounds of formula (I), and one or two
additional groups selected from the group consisting of:
--SF.sub.5, --OSF.sub.5, and --Si(R.sup.15A).sub.3 (wherein each
R.sup.15A is independently selected) are also present in the
compounds of formula (I).
[0177] In another embodiment of this invention one --SF.sub.5 group
is present in the compounds of formula (I), and one or two
additional groups selected from the group consisting of:
--OSF.sub.5, and --Si(R.sup.15A).sub.3 (wherein each R.sup.15A is
independently selected) are also present in the compounds of
formula (I).
[0178] In another embodiment of this invention one --OSF.sub.5
group is present in the compounds of formula (I), and one or two
additional groups selected from the group consisting of:
--SF.sub.5, --OSF.sub.5, and --Si(R.sup.15A).sub.3 (wherein each
R.sup.15A is independently selected) are also present in the
compounds of formula (I).
[0179] In another embodiment of this invention one --OSF.sub.5
group is present in the compounds of formula (I), and one or two
additional groups selected from the group consisting of: --SF.sub.5
and --Si(R.sup.15A).sub.3 (wherein each R.sup.15A is independently
selected) are also present in the compounds of formula (I).
[0180] In another embodiment of this invention one --SF.sub.5 group
is present in the compounds of formula (I), and one or two
additional groups selected from the group consisting of: --SF.sub.5
and --OSF.sub.5 are also present in the compounds of formula
(I).
[0181] In another embodiment of this invention one --OSF.sub.5
group is present in the compounds of formula (I), and one or two
additional groups selected from the group consisting of: --SF.sub.5
and --OSF.sub.5 are also present in the compounds of formula
(I).
[0182] In another embodiment of this invention one
--Si(R.sup.15A).sub.3 (wherein each R.sup.15A is independently
selected) group is present in the compounds of formula (I), and one
or two groups selected from the group consisting of: --SF.sub.5,
--OSF.sub.5, and --Si(R.sup.15A).sub.3 (wherein each R.sup.15A is
independently selected) are also present in the compounds of
formula (I).
[0183] In another embodiment of this invention one
--Si(R.sup.15A).sub.3 (wherein each R.sup.15A is independently
selected) group is present in the compounds of formula (I), and one
or two groups selected from the group consisting of: --SF.sub.5 and
--OSF.sub.5 are also present in the compounds of formula (I).
[0184] In another embodiment of this invention at least one group
selected from the group consisting of: --SF.sub.5, --OSF.sub.5, and
--Si(R.sup.15A).sub.3 (wherein each R.sup.15A is independently
selected from the group consisting of alkyl (e.g., methyl and
ethyl) and aryl (e.g., phenyl)) is present in the compounds of
formula (I).
[0185] In another embodiment of this invention at least one group
selected from the group consisting of: --SF.sub.5, --OSF.sub.5, and
--Si(R.sup.15A).sub.3 (wherein each R.sup.15A is independently
selected from the group consisting of alkyl (e.g., methyl and
ethyl) and phenyl) is present in the compounds of formula (I).
[0186] In another embodiment of this invention at least one group
selected from the group consisting of: --SF.sub.5, --OSF.sub.5, and
--Si(R.sup.15A).sub.3 (wherein each R.sup.15A is independently
selected from the group consisting of methyl, ethyl and phenyl) is
present in the compounds of formula (I).
[0187] In another embodiment of this invention at least one group
selected from the group consisting of: --SF.sub.5, --OSF.sub.5,
--Si(CH.sub.3).sub.3, --Si(CH.sub.3).sub.2-phenyl, and
--Si(CH.sub.2CH.sub.3).sub.2CH.sub.3) is present in the compounds
of formula (I).
[0188] In another embodiment of this invention at least one group
selected from the group consisting of: --SF.sub.5, --OSF.sub.5, and
--Si(CH.sub.3).sub.3 is present in the compounds of formula
(I).
[0189] In another embodiment of this invention one group selected
from the group consisting of: --SF.sub.5, --OSF.sub.5, and
--Si(R.sup.15A).sub.3 (wherein each R.sup.15A is independently
selected) is present in the compounds of formula (I).
[0190] In another embodiment of this invention one group selected
from the group consisting of: --SF.sub.5, --OSF.sub.5, and
--Si(R.sup.15A).sub.3 (wherein each R.sup.15A is independently
selected from the group consisting of alkyl (e.g., methyl and
ethyl) and aryl (e.g., phenyl)) is present in the compounds of
formula (I).
[0191] In another embodiment of this invention one group selected
from the group consisting of: --SF.sub.5, --OSF.sub.5, and
--Si(R.sup.15A).sub.3 (wherein each R.sup.15A is independently
selected from the group consisting of alkyl (e.g., methyl and
ethyl) and phenyl) is present in the compounds of formula (I).
[0192] In another embodiment of this invention one group selected
from the group consisting of: --SF.sub.5, --OSF.sub.5, and
--Si(R.sup.15A).sub.3 (wherein each R.sup.15A independently
selected from the group consisting of methyl, ethyl and phenyl) is
present in the compounds of formula (I).
[0193] In another embodiment of this invention one group selected
from the group consisting of: --SF.sub.5, --OSF.sub.5,
--Si(CH.sub.3).sub.3, --Si(CH.sub.3).sub.2-phenyl, and
--Si(CH.sub.2CH.sub.3).sub.2CH.sub.3) is present in the compounds
of formula (I).
[0194] In another embodiment of this invention one group selected
from the group consisting of: --SF.sub.5, --OSF.sub.5,
--Si(CH.sub.3).sub.3, and --Si(CH.sub.2CH.sub.3).sub.2CH.sub.3) is
present in the compounds of formula (I).
[0195] In another embodiment of this invention one group selected
from the group consisting of: --SF.sub.5, --OSF.sub.5, and
--Si(CH.sub.3).sub.3, is present in the compounds of formula
(I).
[0196] In another embodiment of this invention two groups selected
from the group consisting of: --SF.sub.5, --OSF.sub.5, and
--Si(R.sup.15A).sub.3 (wherein each R.sup.15A is independently
selected) are present in the compounds of formula (I).
[0197] In another embodiment of this invention two groups
independently selected from the group consisting of: --SF.sub.5,
--OSF.sub.5, and --Si(R.sup.15A).sub.3 (wherein each R.sup.15A is
independently selected from the group consisting of alkyl (e.g.,
methyl and ethyl) and aryl (e.g., phenyl)) are present in the
compounds of formula (I).
[0198] In another embodiment of this invention two groups
independently selected from the group consisting of: --SF.sub.5,
--OSF.sub.5, and --Si(R.sup.15A).sub.3 (wherein each R.sup.15A is
independently selected from the group consisting of alkyl (e.g.,
methyl and ethyl) and phenyl) are present in the compounds of
formula (I).
[0199] In another embodiment of this invention two groups selected
from the group consisting of: --SF.sub.5, --OSF.sub.5, and
--Si(R.sup.15A).sub.3 (wherein each R.sup.15A is independently
selected from the group consisting of methyl, ethyl and phenyl) are
present in the compounds of formula (I).
[0200] In another embodiment of this invention two groups
independently selected from the group consisting of: --SF.sub.5,
--OSF.sub.5, --Si(CH.sub.3).sub.3, --Si(CH.sub.3).sub.2-phenyl, and
--Si(CH.sub.2CH.sub.3).sub.2CH.sub.3) is present in the compounds
of formula (I).
[0201] In another embodiment of this invention two groups
independently selected from the group consisting of: --SF.sub.5,
--OSF.sub.5, --Si(CH.sub.3).sub.3, and
--Si(CH.sub.2CH.sub.3).sub.2CH.sub.3) are present in the compounds
of formula (I).
[0202] In another embodiment of this invention two groups
independently selected from the group consisting of: --SF.sub.5,
--OSF.sub.5, and --Si(C.sub.1-13).sub.3 are present in the
compounds of formula (I).
[0203] In another embodiment of this invention three groups
selected from the group consisting of: --SF.sub.5, --OSF.sub.5, and
--Si(R.sup.15A).sub.3 (wherein each R.sup.15A is independently
selected) are present in the compounds of formula (I)I.
[0204] In another embodiment of this invention three groups
independently selected from the group consisting of: --SF.sub.5,
--OSF.sub.5, and --Si(R.sup.15A).sub.3 (wherein each R.sup.15A is
independently selected from the group consisting of alkyl (e.g.,
methyl and ethyl) and aryl (e.g., phenyl)) are present in the
compounds of formula (I).
[0205] In another embodiment of this invention three groups
independently selected from the group consisting of: --SF.sub.5,
--OSF.sub.5, and --Si(R.sup.15A).sub.3 (wherein each R.sup.15A is
independently selected from the group consisting of alkyl (e.g.,
methyl and ethyl) and phenyl) are present in the compounds of
formula (I).
[0206] In another embodiment of this invention three groups
selected from the group consisting of: --SF.sub.5, --OSF.sub.5, and
--Si(R.sup.15A).sub.3 (wherein each R.sup.15A is independently
selected from the group consisting of methyl, ethyl and phenyl) are
present in the compounds of formula (I).
[0207] In another embodiment of this invention three groups
independently selected from the group consisting of: --SF.sub.5,
--OSF.sub.5, --Si(CH.sub.3).sub.3, --Si(CH.sub.3).sub.2phenyl, and
--Si(CH.sub.2CH.sub.3).sub.2CH.sub.3) is present in the compounds
of formula (I).
[0208] In another embodiment of this invention three groups
independently selected from the group consisting of: --SF.sub.5,
--OSF.sub.5, --Si(CH.sub.3).sub.3, and
--Si(CH.sub.2CH.sub.3).sub.2CH.sub.3) are present in the compounds
of formula (I).
[0209] In another embodiment of this invention three groups
independently selected from the group consisting of: --SF.sub.5,
--OSF.sub.5, and --Si(CH.sub.3).sub.3 are present in the compounds
of formula (I).
[0210] In another embodiment of this invention at least one group
selected from the group consisting of: --SF.sub.5, --OSF.sub.5, and
--Si(R.sup.15A).sub.3 (wherein each R.sup.15A is the same or
different alkyl group) is present in the compounds of formula
(O.
[0211] In another embodiment of this invention at least one group
selected from the group consisting of: --SF.sub.5, --OSF.sub.5, and
--Si(R.sup.15A).sub.3 (wherein each R.sup.15A is independently
selected from the group consisting of methyl and ethyl) is present
in the compounds of formula (I).
[0212] In another embodiment of this invention one --SF.sub.5 group
is present in the compounds of formula (I), and one or two groups
selected from the group consisting of: --SF.sub.5 and --OSF.sub.5
are also present in the compounds of formula (I).
[0213] In another embodiment of this invention one --OSF.sub.5
group is present in the compounds of formula (I), and one or two
groups selected from the group consisting of: --SF.sub.5 and
--OSF.sub.5 are also present in the compounds of formula (I).
[0214] Those skilled in the art will appreciate that when W is
--S(O)--, the --S(O)-moiety can be:
##STR00016##
or the --S(O)-moiety can be;
##STR00017##
[0216] The compounds of formula (I) do not have three consecutive
nitrogen atoms in the ring. Thus, including the nitrogen to which
R.sup.1 is bound, there are up to two additional nitrogens in the
ring (i.e., up to two --N(R.sup.2).sub.d-- groups in the ring)
provided that the nitrogens are not in consecutive ring positions.
Thus, (a) when G.sup.1 is --N(R.sup.2).sub.d-- then G.sup.2 is not
--N(R.sup.2).sub.d--, and (b) when G.sup.3 is --N(R.sup.2).sub.d--
and G.sup.2 is --N(R.sup.2).sub.d-- then G.sup.1 is not
--N(R.sup.2).sub.d--, and (c) when G.sup.3 is --N(R.sup.2).sub.d--
and G.sup.1 is --N(R.sup.2).sub.d-- then G.sup.2 is not
--N(R.sup.2).sub.d--).
[0217] In formula (I), 0 to 2 of the G.sup.1, G.sup.2, G.sup.3, and
G.sup.4 moieties are --N(R.sup.2).sub.d-- wherein each d and each
R.sup.2 is independently selected. Thus Ring (A) in formula (I)
comprises a total of 1 to 3 nitrogen atoms (the --NR.sup.1-moiety
and 0 to 2 --N(R.sup.2).sub.d-moieties) in the ring such that the
Ring (A) does not comprise three consecutive ring nitrogens, and
each d and each R.sup.2 is independently selected.
[0218] One embodiment of this invention is directed to compounds of
formula (IA):
##STR00018##
[0219] Another embodiment of this invention is directed to
compounds of formula (IB):
##STR00019##
[0220] Another embodiment of this invention is directed to
compounds of formula (IA) having the formula:
##STR00020##
[0221] Another embodiment of this invention is directed to
compounds of formula (IB) having the formula:
##STR00021##
[0222] In another embodiment of this invention G.sup.1 is
--C(R.sup.21).sub.q--.
[0223] In another embodiment of this invention G.sup.1 is
--N(R.sup.2).sub.d--.
[0224] In another embodiment of this invention G.sup.1 is a direct
bond.
[0225] In another embodiment of this invention G.sup.1 is
--O--.
[0226] In another embodiment of this invention G.sup.1 is
--S--.
[0227] In another embodiment of this invention G.sup.2 is
--C(R.sup.21).sub.q--.
[0228] In another embodiment of this invention G.sup.2 is
--N(R.sup.2).sub.d--.
[0229] In another embodiment of this invention G.sup.2 is a direct
bond.
[0230] In another embodiment of this invention G.sup.2 is
--O--.
[0231] In another embodiment of this invention G.sup.2 is
--S--.
[0232] In another embodiment of this invention W is --C(O)--.
[0233] In another embodiment of this invention W is --S(O)--.
[0234] In another embodiment of this invention W is
--S(O).sub.2--.
[0235] In another embodiment of this invention W is
--C(.dbd.NR.sup.2)--.
[0236] In another embodiment of this invention G.sup.1 is
--N(R.sup.2).sub.d--, and W is --C(O)--.
[0237] In another embodiment of this invention G.sup.1 is --C(O)--,
and W is --C(O)--.
[0238] In another embodiment of this invention G.sup.1 is --S(O)--,
and W is --C(O)--.
[0239] In another embodiment of this invention G.sup.1 is
--S(O).sub.2--, and W is --C(O)--.
[0240] In another embodiment of this invention G.sup.1 is
--C(.dbd.NR.sup.2)--, and W is --C(O)--.
[0241] In another embodiment of this invention G.sup.1 is
--C(N(R.sup.2).sub.2)-- wherein each R.sup.2 is independently
selected, and W is --C(O)--.
[0242] In another embodiment of this invention G.sup.1 is a direct
bond, and W is --C(O)--.
[0243] In another embodiment of this invention G.sup.1 is --O--,
and W is --C(O)--.
[0244] In another embodiment of this invention G.sup.1 is --S--,
and W is --C(O)--.
[0245] In another embodiment of this invention G.sup.2 is
--C(R.sup.21).sub.q--, and W is --C(O)--.
[0246] In another embodiment of this invention G.sup.2 is
--N(R.sup.2).sub.d--, and W is --C(O)--.
[0247] In another embodiment of this invention G.sup.2 is --C(O)--,
and W is --C(O)--.
[0248] In another embodiment of this invention G.sup.2 is --S(O)--,
and W is --C(O)--.
[0249] In another embodiment of this invention G.sup.2 is
--S(O).sub.2--, and W is --C(O)--.
[0250] In another embodiment of this invention G.sup.2 is
--C(.dbd.NR.sup.2)--, and W is --C(O)--.
[0251] In another embodiment of this invention G.sup.2 is
--C(N(R.sup.2).sub.2)-- wherein each R.sup.2 is independently
selected, and W is --C(O)--.
[0252] In another embodiment of this invention G.sup.2 is a direct
bond, and W is --C(O)--.
[0253] In another embodiment of this invention G.sup.2 is --O--,
and W is --C(O)--.
[0254] In another embodiment of this invention G.sup.2 is --S--,
and W is --C(O)--.
[0255] In another embodiment of this invention G.sup.5 is
--CH--.
[0256] In another embodiment of this invention G.sup.5 is
--NH--.
[0257] In another embodiment of this invention G.sup.5 is
--N.dbd..
[0258] In another embodiment of this invention G.sup.5 is
--O--.
[0259] In another embodiment of this invention G.sup.5 is
--S--.
[0260] In another embodiment of this invention G.sup.5 is
--S(O)--.
[0261] In another embodiment of this invention G.sup.5 is
--S(O).sub.2--.
[0262] In another embodiment of this invention G.sup.6 is C.
[0263] In another embodiment of this invention G.sup.6 is CH.
[0264] In another embodiment of this invention G.sup.5 is --CH--,
and G.sup.6 is C.
[0265] In another embodiment of this invention G.sup.5 is --NH--,
and G.sup.6 is C.
[0266] In another embodiment of this invention G.sup.5 is --N.dbd.,
and G.sup.5 is C.
[0267] In another embodiment of this invention G.sup.6 is --O--,
and G.sup.6 is C.
[0268] In another embodiment of this invention G.sup.5 is --S--,
and G.sup.6 is C.
[0269] In another embodiment of this invention G.sup.5 is --S(O)--,
and G.sup.6 is C.
[0270] In another embodiment of this invention G.sup.5 is
--S(O).sub.2--, and G.sup.6 is C.
[0271] In another embodiment of this invention G.sup.5 is --CH--,
and G.sup.6 is CH.
[0272] In another embodiment of this invention G.sup.5 is --NH--,
and G.sup.6 is CH.
[0273] In another embodiment of this invention G.sup.5 is --N.dbd.,
and G.sup.6 is CH.
[0274] In another embodiment of this invention G.sup.5 is --O--,
and G.sup.6 is CH.
[0275] In another embodiment of this invention G.sup.5 is --S--,
and G.sup.6 is CH.
[0276] In another embodiment of this invention G.sup.5 is --S(O)--,
and G.sup.6 is CH.
[0277] In another embodiment of this invention G.sup.5 is
--S(O).sub.2--, and G.sup.6 is CH.
[0278] In another embodiment of this invention G.sup.7 is a direct
bond (i.e., R.sup.10 is bound directly to G.sup.6).
[0279] In another embodiment of this invention G.sup.7 is
--C(O)--.
[0280] In another embodiment of this invention G.sup.7 is
--(C.dbd.NR.sup.2)--.
[0281] In another embodiment of this invention G.sup.7 is
--CHR.sup.3--.
[0282] In another embodiment of this invention G.sup.7 is
C(R.sup.4).sub.2.
[0283] In another embodiment of this invention G.sup.7 is
--CF.sub.2--.
[0284] In another embodiment of this invention G.sup.7 is
--N(R.sup.2)--.
[0285] In another embodiment of this invention G.sup.7 is
--O--.
[0286] In another embodiment of this invention G.sup.7 is
--S--.
[0287] In another embodiment of this invention G.sup.7 is
--S(O).sub.t.
[0288] In another embodiment of this invention G.sup.7 is
--CR.sup.4(OH)--.
[0289] In another embodiment of this invention G.sup.7 is
--CR.sup.4(OR.sup.4)--.
[0290] In another embodiment of this invention G.sup.7 is
--C.dbd.C--.
[0291] In another embodiment of this invention G.sup.7 is
alkynyl.
[0292] In another embodiment of this invention G.sup.7 is
--(CH.sub.2).sub.rN(R.sup.2)--.
[0293] In another embodiment of this invention G.sup.7 is
--(CHR.sup.4).sub.rN(R.sup.2)--.
[0294] In another embodiment of this invention G.sup.7 is
--(C(R.sup.4).sub.2).sub.rN(R.sup.2)--.
[0295] In another embodiment of this invention G.sup.7 is
--N(R.sup.2)(CH.sub.2).sub.r--.
[0296] In another embodiment of this invention G.sup.7 is
--N(R.sup.2)(CHR.sup.4).sub.r--.
[0297] In another embodiment of this invention G.sup.7 is
--N(R.sup.2)(C(R.sup.4).sub.2).sub.r--.
[0298] In another embodiment of this invention G.sup.7 is
--(CH.sub.2).sub.r--O--.
[0299] In another embodiment of this invention G.sup.7 is
--(CHR.sup.4).sub.r--O--.
[0300] In another embodiment of this invention G.sup.7 is
--(C(R.sup.4).sub.2).sub.r--O--.
[0301] In another embodiment of this invention G.sup.7 is
--O--(CH.sub.2).sub.r--.
[0302] In another embodiment of this invention G.sup.7 is
--O--(CHR.sup.4).sub.r--.
[0303] In another embodiment of this invention G.sup.7 is
--O--(C(R.sup.4).sub.2).sub.r--.
[0304] In another embodiment of this invention G.sup.7 is
--C(O)NR.sup.5--.
[0305] In another embodiment of this invention G.sup.7 is
--O--C(O)--.
[0306] In another embodiment of this invention G.sup.7 is
--C(O)--O--.
[0307] In another embodiment of this invention G.sup.7 is
--O--C(O)--NR.sup.5--.
[0308] In another embodiment of this invention G.sup.7 is
--NR.sup.5C(O)--.
[0309] In another embodiment of this invention G.sup.7 is
--(CH.sub.2).sub.rNR.sup.5--C(O)--.
[0310] In another embodiment of this invention G.sup.7 is
--(CHR.sup.4).sub.rNR.sup.5--C(O)--.
[0311] In another embodiment of this invention G.sup.7 is
--(C(R.sup.4).sub.2).sub.rNR.sup.5--C(O)--.
[0312] In another embodiment of this invention G.sup.7 is
--C(O)NR.sup.5(CH.sub.2).sub.r--.
[0313] In another embodiment of this invention G.sup.7 is
--C(O)NR.sup.5 (CHR.sup.4).sub.r--.
[0314] In another embodiment of this invention G.sup.7 is
--C(O)NR.sup.5 (C(R.sup.4).sub.2).sub.r--.
[0315] In another embodiment of this invention G.sup.7 is
--NR.sup.5S(O).sub.t--.
[0316] In another embodiment of this invention G.sup.7 is
--(CH.sub.2).sub.rNR.sup.5S(O).sub.r.
[0317] In another embodiment of this invention G.sup.7 is
--(CHR.sup.4).sub.rNR.sup.5S(O).sub.t--.
[0318] In another embodiment of this invention G.sup.7 is
--(C(R.sup.4).sub.2).sub.rNR.sup.5S(O).sub.t--.
[0319] In another embodiment of this invention G.sup.7 is
--S(O).sub.tNR.sup.5--.
[0320] In another embodiment of this invention G.sup.7 is
--S(O).sub.tNR.sup.5(CH.sub.2).sub.r--.
[0321] In another embodiment of this invention G.sup.7 is
--S(O).sub.tNR.sup.5(CHR.sup.4).sub.r--.
[0322] In another embodiment of this invention G.sup.7 is
--S(O).sub.tNR.sup.5(C(R.sup.4).sub.2).sub.r--.
[0323] In another embodiment of this invention G.sup.7 is
--NR.sup.5--C(O)--O--.
[0324] In another embodiment of this invention G.sup.7 is
--NR.sup.5--C(O)--NR.sup.5--.
[0325] In another embodiment of this invention G.sup.7 is
--NR.sup.5--S(O).sub.rNR.sup.5--.
[0326] In another embodiment of this invention G.sup.7 is
--NR.sup.5--C(.dbd.NR.sup.2)--NR.sup.5--.
[0327] In another embodiment of this invention G.sup.7 is
--NR.sup.5--C(.dbd.NR.sup.2)--O--.
[0328] In another embodiment of this invention G.sup.7 is
--O--C(.dbd.NR.sup.2)--NR.sup.5--.
[0329] In another embodiment of this invention G.sup.7 is
--C(R.sup.4).dbd.N--O--.
[0330] In another embodiment of this invention G.sup.7 is
--O--N.dbd.C(R.sup.4)--.
[0331] In another embodiment of this invention G.sup.7 is
--O--C(R.sup.4).dbd.N--.
[0332] In another embodiment of this invention G.sup.7 is
--N.dbd.C(R.sup.4)--O--.
[0333] In another embodiment of this invention G.sup.7 is
--(CH.sub.2).sub.2--.
[0334] In another embodiment of this invention G.sup.7 is
--(C(R.sup.4).sub.2).sub.2--.
[0335] In another embodiment of this invention G.sup.7 is
--(CHR.sup.4).sub.2--.
[0336] In another embodiment of this invention G.sup.7 is
--(CH.sub.2).sub.3--.
[0337] In another embodiment of this invention G.sup.7 is
--(C(R.sup.4).sub.2).sub.3--.
[0338] In another embodiment of this invention G.sup.7 is
--(CHR.sup.4).sub.3--.
[0339] In another embodiment of this invention G.sup.7 is
cycloalkyl.
[0340] In another embodiment of this invention G.sup.7 is
heterocycloalkyl.
[0341] In another embodiment of this invention t is 1.
[0342] In another embodiment of this invention t is 2.
[0343] In another embodiment of this invention r is 1.
[0344] In another embodiment of this invention r is 2.
[0345] In another embodiment of this invention r is 3.
[0346] In another embodiment of this invention Ring (E) is a five
membered heteroaryl ring.
[0347] In another embodiment of this invention Ring (E) is a six
membered heteroaryl ring.
[0348] In another embodiment of this invention Ring (E) is a five
membered heterocycloalkyl ring.
[0349] In another embodiment of this invention Ring (E) is a six
membered heterocycloalkyl ring.
[0350] In another embodiment of this invention Ring (E) is a five
membered heterocycloalkenyl ring,
[0351] In another embodiment of this invention Ring (E) is a six
membered heterocycloalkenyl ring.
[0352] In another embodiment of this invention Ring (F) is a five
membered heteroaryl ring.
[0353] In another embodiment of this invention Ring (F) is a six
membered heteroaryl ring.
[0354] In another embodiment of this invention Ring (F) is a five
membered heterocycloalkyl ring.
[0355] In another embodiment of this invention Ring (F) is a six
membered heterocycloalkyl ring.
[0356] In another embodiment of this invention Ring (F) is a five
membered heterocycloalkenyl ring.
[0357] In another embodiment of this invention Ring (F) is a six
membered heterocycloalkenyl ring.
[0358] In another embodiment of this invention G.sup.5 is --CH--,
and G.sup.6 is C, and Ring (E) or Ring (F) is a five membered
heteroaryl ring.
[0359] In another embodiment of this invention G.sup.5 is --NH--,
and G.sup.6 is C, and Ring (E) or Ring (F) is a five membered
heteroaryl ring.
[0360] In another embodiment of this invention G.sup.5 is --N.dbd.,
and G.sup.6 is C, and Ring (E) or Ring (F) is a five membered
heteroaryl ring.
[0361] In another embodiment of this invention G.sup.5 is --O--,
and G.sup.6 is C, and Ring (E) or Ring (F) is a five membered
heteroaryl ring.
[0362] In another embodiment of this invention G.sup.5 is --S--,
and G.sup.6 is C, and Ring (E) or Ring (F) is a five membered
heteroaryl ring.
[0363] In another embodiment of this invention G.sup.5 is --S(O)--,
and G.sup.6 is C, and Ring (E) or Ring (F) is a five membered
heteroaryl ring.
[0364] In another embodiment of this invention G.sup.5 is
--S(O).sub.2--, and G.sup.6 is C, and Ring (E) or Ring (F) is a
five membered heteroaryl ring.
[0365] In another embodiment of this invention G.sup.5 is --CH--,
and G.sup.6 is C, and Ring (E) or Ring (F) is a six membered
heteroaryl ring.
[0366] In another embodiment of this invention G.sup.5 is --NH--,
and G.sup.6 is C, and Ring (E) or Ring (F) is a six membered
heteroaryl ring.
[0367] In another embodiment of this invention G.sup.5 is --N.dbd.,
and G.sup.6 is C, and Ring (E) or Ring (F) is a six membered
heteroaryl ring.
[0368] In another embodiment of this invention G.sup.5 is --O--,
and G.sup.6 is C, and Ring (E) or Ring (F) is a six membered
heteroaryl ring.
[0369] In another embodiment of this invention G.sup.5 is --S--,
and G.sup.6 is C, and Ring (E) or Ring (F) is a six membered
heteroaryl ring.
[0370] In another embodiment of this invention G.sup.5 is --S(O)--,
and G.sup.6 is C, and Ring (E) or Ring (F) is a six membered
heteroaryl ring.
[0371] In another embodiment of this invention G.sup.5 is
--S(O).sub.2--, and G.sup.6 is C, and Ring (E) or Ring (F) is a six
membered heteroaryl ring.
[0372] In another embodiment of this invention G.sup.5 is --CH--,
and G.sup.6 is CH, and Ring (E) or Ring (F) is a five membered
heterocycloalkyl ring.
[0373] In another embodiment of this invention G.sup.5 is --NH--,
and G.sup.6 is CH, and Ring (E) or Ring (F) is a five membered
heterocycloalkyl ring.
[0374] In another embodiment of this invention G.sup.5 is --N.dbd.,
and G.sup.6 is CH, and Ring (E) or Ring (F) is a five membered
heterocycloalkyl ring.
[0375] In another embodiment of this invention G.sup.5 is --O--,
and G.sup.6 is CH, and Ring (E) or Ring (F) is a five membered
heterocycloalkyl ring.
[0376] In another embodiment of this invention G.sup.5 is --S--,
and G.sup.6 is CH, and Ring (E) or Ring (F) is a five membered
heterocycloalkyl ring.
[0377] In another embodiment of this invention G.sup.5 is --S(O)--,
and G.sup.6 is CH, and Ring (E) or Ring (F) is a five membered
heterocycloalkyl ring.
[0378] In another embodiment of this invention G.sup.5 is
--S(O).sub.2--, and G.sup.6 is CH, and Ring (E) or Ring (F) is a
five membered heterocycloalkyl ring.
[0379] In another embodiment of this invention G.sup.5 is --CH--,
and G.sup.6 is CH, and Ring (E) or Ring (F) is a six membered
heterocycloalkyl ring.
[0380] In another embodiment of this invention G.sup.5 is --NH--,
and G.sup.6 is CH, and Ring (E) or Ring (F) is a six membered
heterocycloalkyl ring,
[0381] In another embodiment of this invention G.sup.5 is --N.dbd.,
and G.sup.6 is CH, and Ring (E) or Ring (F) is a six membered
heterocycloalkyl ring.
[0382] In another embodiment of this invention G.sup.5 is --O--,
and G.sup.6 is CH, and Ring (E) or Ring (F) is a six membered
heterocycloalkyl ring.
[0383] In another embodiment of this invention G.sup.5 is --S--,
and G.sup.6 is CH, and Ring (E) or Ring (F) is a six membered
heterocycloalkyl ring.
[0384] In another embodiment of this invention G.sup.5 is --S(O)--,
and G.sup.6 is CH, and Ring (E) or Ring (F) is a six membered
heterocycloalkyl ring.
[0385] In another embodiment of this invention G.sup.5 is
--S(O).sub.2--, and G.sup.6 is CH, and Ring (E) or Ring (F) is a
six membered heterocycloalkyl ring.
[0386] In another embodiment of this invention G.sup.5 is --CH--,
and G.sup.6 is CH.
[0387] In another embodiment of this invention G.sup.s is --NH--,
and G.sup.6 is CH.
[0388] In another embodiment of this invention G.sup.5 is --N.dbd.,
and G.sup.6 is CH.
[0389] In another embodiment of this invention G.sup.5 is --O--,
and G.sup.6 is CH.
[0390] In another embodiment of this invention G.sup.5 is --S--,
and G.sup.6 is CH.
[0391] In another embodiment of this invention G.sup.5 is --S(O)--,
and G.sup.6 is CH.
[0392] In another embodiment of this invention G.sup.5 is
--S(O).sub.2--, and G.sup.6 is CH.
[0393] Other embodiments of this invention are directed to
compounds of formula (IA) wherein G.sup.5, G.sup.6 and G.sup.7 are
as described in any of the above embodiments directed to G.sup.5,
G.sup.6 and G.sup.7.
[0394] Other embodiments of this invention are directed to
compounds of formula (IB) wherein G.sup.5, G.sup.6 and G.sup.7 are
as described in any of the above embodiments directed to G.sup.5,
G.sup.6 and G.sup.7.
[0395] In another embodiment of this invention R.sup.21 is selected
from the group consisting of: alkyl, --OR.sup.15, --C(O)OR.sup.15,
--C(O)NR.sup.15R.sup.16, and alkyl substituted with 1 to 5
independently selected R.sup.22 groups (e.g., halo, such as, for
example, F, Cl, and Br).
[0396] In another embodiment of this invention R.sup.21 is selected
from the group consisting of: alkyl, --OR.sup.15, --C(O)OR.sup.15,
--C(O)NR.sup.15R.sup.16, and alkyl substituted with 1 to 5
independently selected R.sup.22 groups (e.g., halo, such as, for
example, F, Cl, and Br, and wherein in one example the alkyl
substituted R.sup.21 group is --CF.sub.3), wherein R.sup.15 and
R.sup.16 are independently selected from the group consisting of:
H, alkyl, (R.sup.18).sub.n-arylalkyl- (wherein, for example, n is
1, and R.sup.18 is --OR.sup.20, and R.sup.20 is alkyl (e.g.,
methyl), cycloalkyl (e.g., cyclobutyl), and (R.sup.18).sub.n-alkyl
(e.g., n is 1, R.sup.18 is --OR.sup.20, and R.sup.20 is alkyl
(e.g., methyl).
[0397] In another embodiment of this invention R.sup.21 is selected
from the group consisting of: (a) alkyl, --OR.sup.16 (wherein
R.sup.15 is alkyl, e.g., methyl and ethyl), (b) --C(O)OR.sup.15
(wherein R.sup.15 is alkyl, e.g., methyl), (c)
--C(O)NR.sup.15R.sup.16 (wherein R.sup.15 and R.sup.16 are
independently selected from the group consisting of: H, alkyl,
(R.sup.18).sub.n-arylalkyl- (wherein, for example, n is 1, and
R.sup.18 is --OR.sup.20, and R.sup.20 is alkyl (e.g., methyl),
cycloalkyl (e.g., cyclobutyl), and (R.sup.18).sub.n-alkyl (e.g., n
is 1, R.sup.18 is --OR.sup.20, and R.sup.20 is alkyl (e.g.,
methyl), and in one example, only one of R.sup.15 and R.sup.16 is
H), and (d) alkyl substituted with 1 to 5 independently selected
R.sup.22 groups (e.g., halo, such as, for example, F, Cl, and Br,
and wherein in one example the alkyl substituted R.sup.21 group is
--CF.sub.3).
[0398] In one embodiment of this invention R.sup.10 is selected
from the group consisting of: aryl- (e.g., phenyl), heteroaryl-
(e.g., pyridyl), cycloalkyl-, cycloalkenyl, cycloalkylalkyl-,
heterocyclyl-, heterocyclenyl-, heterocyclylalkyl-,
heterocyclyalkenyl-, fused benzocycloalkyl- (i.e.,
benzofusedcycloalkyl-), fused benzoheterocycloalkyl- (i.e.,
benzofusedheterocycloalkyl-), fused heteroarylcycloalkyl- (i.e.,
heteroarylfusedcycloalkyl-), fused heteroarylheterocycloalkyl-
(i.e., heteroarylfusedheterocycloalkyl-), fused cycloalkylaryl
(i.e., cycloalkyfusedlaryl-), fused heterocycloalkylaryl- (i.e.,
heterocycloalkylfusedaryl-), fused cycloalkylheteroaryl- (i.e.,
cycloalkylfusedheteroaryl-), and fused heterocycloalkylheteroaryl-
(i.e., heterocycloalkylfusedheteroaryl-), and wherein each of said
R.sup.10 moieties is optionally substituted with 1-5 independently
selected R.sup.21 groups.
[0399] In another embodiment of this invention R.sup.10 is selected
from the group consisting of:
##STR00022##
wherein X is selected from the group consisting of: O,
--N(R.sup.14)-- and --S--; and wherein each of said R.sup.10
moieties is optionally substituted with 1-5 independently selected
R.sup.21 groups.
[0400] In another embodiment of this invention R.sup.10 is selected
from the group consisting of:
##STR00023## ##STR00024##
wherein each of said R.sup.10 moieties is optionally substituted
with 1-5 independently selected R.sup.21 groups.
[0401] In another embodiment of this invention R.sup.10 in formula
(I) is selected from the group consisting of:
##STR00025## ##STR00026## ##STR00027## ##STR00028## ##STR00029##
##STR00030##
[0402] In another embodiment of this invention R.sup.10 is group
1AA. In another embodiment of this invention R.sup.10 is group 2AA.
In another embodiment of this invention R.sup.10 is group 3AA. In
another embodiment of this invention R.sup.10 is group 4AA. In
another embodiment of this invention R.sup.10 is group 5AA. In
another embodiment of this invention R.sup.10 is group 6AA. In
another embodiment of this invention R.sup.10 is group 7AA. In
another embodiment of this invention R.sup.10 is group 5AA. In
another embodiment of this invention R.sup.10 is group 9AA. In
another embodiment of this invention R.sup.10 is group 10AA. In
another embodiment of this invention R.sup.10 is group 11AA. In
another embodiment of this invention R.sup.10 is group 12AA. In
another embodiment of this invention R.sup.10 is group 13AA. In
another embodiment of this invention R.sup.10 is group 14AA. In
another embodiment of this invention R.sup.10 is group 15AA. In
another embodiment of this invention R.sup.10 is group 16AA. In
another embodiment of this invention R.sup.10 is group 17AA. In
another embodiment of this invention R.sup.10 is group 18AA. In
another embodiment of this invention R.sup.10 is group 19AA. In
another embodiment of this invention R.sup.10 is group 20AA. In
another embodiment of this invention R.sup.10 is group 21AA. In
another embodiment of this invention R.sup.10 is group 22AA. In
another embodiment of this invention R.sup.10 is group 23AA. In
another embodiment of this invention R.sup.10 is group 24AA. In
another embodiment of this invention R.sup.10 is group 25AA. In
another embodiment of this invention R.sup.10 is group 26AA. In
another embodiment of this invention R.sup.10 is group 27AA. In
another embodiment of this invention R.sup.10 is group 28AA. In
another embodiment of this invention R.sup.10 is group 29AA. In
another embodiment of this invention R.sup.10 is group 30AA. In
another embodiment of this invention R.sup.10 is group 31AA. In
another embodiment of this invention R.sup.10 is group 32AA. In
another embodiment of this invention R.sup.10 is group 33AA. In
another embodiment of this invention R.sup.10 is group 34AA. In
another embodiment of this invention R.sup.10 is group 35AA. In
another embodiment of this invention R.sup.10 is group 36AA. In
another embodiment of this invention R.sup.10 is group 37AA. In
another embodiment of this invention R.sup.10 is group 38AA. In
another embodiment of this invention R.sup.10 is group 39A. In
another embodiment of this invention R.sup.10 is group 40AA. In
another embodiment of this invention R.sup.10 is group 41AA. In
another embodiment of this invention R.sup.10 is group 42AA.
[0403] In another embodiment of this invention R.sup.10 is
aryl.
[0404] In another embodiment of this invention R.sup.10 aryl is
aryl and said aryl is phenyl.
[0405] In another embodiment of this invention R.sup.10 is aryl
substituted with one or more R.sup.21 groups.
[0406] In another embodiment of this invention R.sup.10 is aryl
substituted with one or more R.sup.21 groups, and said aryl is
phenyl, i.e., said R.sup.10 group is phenyl substituted with one or
more R.sup.21 groups.
[0407] In another embodiment of this invention R.sup.10 is phenyl
substituted with one or more R.sup.21 groups, and each R.sup.21
group is the same or different --OR.sup.15 group.
[0408] In another embodiment of this invention R.sup.10 is phenyl
substituted with one or more R.sup.21 groups, and each R.sup.21
group is the same or different --OR.sup.15 group, and said R.sup.15
is alkyl, and each alkyl is independently selected.
[0409] In another embodiment of this invention R.sup.10 is phenyl
substituted with one R.sup.21 group, and said R.sup.21 group is
--OR.sup.15, and said R.sup.15 is alkyl.
[0410] In another embodiment of this invention R.sup.10 is phenyl
substituted with one R.sup.21 group, and said R.sup.21 group is
--OR.sup.15, and said R.sup.15 is alkyl, and said alkyl is
methyl.
[0411] In another embodiment of this invention R.sup.10 is phenyl
substituted with one or more (e.g., one or two, or one)
independently selected R.sup.21 halo groups.
[0412] In another embodiment of this invention R.sup.10 is phenyl
substituted with one R.sup.21 group, and said R.sup.21 group is
halo.
[0413] In another embodiment of this invention R.sup.10 is phenyl
substituted with one R.sup.21 group, and said R.sup.21 group is
F.
[0414] In another embodiment of this invention R.sup.10 is phenyl
substituted with one R.sup.21 group and said R.sup.21 is an
--OR.sup.15 group, and R.sup.15 is an (R.sup.18).sub.nalkyl group,
and R.sup.18 is halo, and it is 1 to 3, and each halo is
independently selected.
[0415] In another embodiment of this invention R.sup.10 is phenyl
substituted with one R.sup.21 group and said R.sup.21 is an
--OR.sup.15 group, and R.sup.15 is an (R.sup.18).sub.nalkyl group,
and R.sup.18 is F, and n is 3.
[0416] In another embodiment of this invention R.sup.10 is phenyl
substituted with one R.sup.21 group and said R.sup.21 is an
--OR.sup.15 group, and R.sup.15 is an (R.sup.18).sub.nalkyl group,
and R.sup.18 is F, and n is 3, and the alkyl is methyl (i.e., the
R.sup.21 substituent is --OCF.sub.3).
[0417] In another embodiment of this invention R.sup.10 is
heteroaryl.
[0418] In another embodiment of this invention R.sup.10 is
heteroaryl substituted with one or more R.sup.21 groups.
[0419] In another embodiment of this invention R.sup.9 is selected
from the group consisting of:
##STR00031## ##STR00032##
[0420] In another embodiment of this invention R.sup.10 is selected
from the group consisting of 1AA to 42AA, and R.sup.9 is selected
from the group consisting of 1gg to 13gg.
[0421] In another embodiment of this invention R.sup.10 is selected
from the group consisting of 1AA to 42AA, and R.sup.9 is 2gg.
[0422] Examples of the R.sup.9-R.sup.10-moiety include, but are not
limited to:
##STR00033## ##STR00034## ##STR00035## ##STR00036## ##STR00037##
##STR00038##
[0423] In another embodiment the R.sup.9-R.sup.10-moiety is 1bb. In
another embodiment the R.sup.9-R.sup.10-moiety is 2bb. In another
embodiment the R.sup.9-R.sup.10-moiety is 3bb. In another
embodiment the R.sup.9-R.sup.10-moiety is 4bb. In another
embodiment the R.sup.9-R.sup.10-moiety is 5bb. In another
embodiment the R.sup.9-R.sup.10-moiety is ebb. In another
embodiment the R.sup.9-R.sup.10-moiety is 7bb. In another
embodiment the R.sup.9-R.sup.10-moiety is ebb. In another
embodiment the R.sup.9-R.sup.10-moiety is 9bb. In another
embodiment the R.sup.9-R.sup.10-moiety is 10bb. In another
embodiment the R.sup.9-R.sup.10-moiety is 11 bb. In another
embodiment the R.sup.9-R.sup.10-moiety is 12bb. In another
embodiment the R.sup.9-R.sup.10-moiety is 13bb. In another
embodiment the R.sup.9-R.sup.10-moiety is 14bb. In another
embodiment the R.sup.9-R.sup.10-moiety is 15bb. In another
embodiment the R.sup.9-R.sup.10-moiety is 16bb. In another
embodiment the R.sup.9-R.sup.10-moiety is 17bb. In another
embodiment the R.sup.9-R.sup.10-moiety is 18bb. In another
embodiment the R.sup.9-R.sup.10-moiety is 19bb. In another
embodiment the R.sup.9-R.sup.10-moiety is 20bb. In another
embodiment the R.sup.9-R.sup.10-moiety is 21 bb. In another
embodiment the R.sup.9-R.sup.10-moiety is 22bb. In another
embodiment the R.sup.9-R.sup.10-moiety is 23bb. In another
embodiment the R.sup.9-R.sup.10-moiety is 24bb. In another
embodiment the R.sup.9-R.sup.10-moiety is 25bb. In another
embodiment the R.sup.9-R.sup.10-moiety is 26bb. In another
embodiment the R.sup.9-R.sup.10-moiety is 27bb. In another
embodiment the R.sup.9-R.sup.10-moiety is 28bb. In another
embodiment the R.sup.9-R.sup.10-moiety is 29bb. In another
embodiment the R.sup.9-R.sup.10-moiety is 30bb. In another
embodiment the R.sup.9-R.sup.10-moiety is 31 bb. In another
embodiment the R.sup.9-R.sup.10-moiety is 32bb. In another
embodiment the R.sup.9-R.sup.10-moiety is 33bb. In another
embodiment the R.sup.9-R.sup.10-moiety is 34bb. In another
embodiment the R.sup.9-R.sup.10-moiety is 35bb. In another
embodiment the R.sup.9-R.sup.10-moiety is 36bb. In another
embodiment the R.sup.9-R.sup.10-moiety is 37bb. In another
embodiment the R.sup.9-R.sup.10-moiety is 38bb. In another
embodiment the R.sup.9-R.sup.10-moiety is 39bb. In another
embodiment the R.sup.9-R.sup.10-moiety is 40bb.
[0424] In another embodiment of this invention R.sup.9 is
heteroaryl.
[0425] In another embodiment of this invention R.sup.9 is
heteroaryl substituted with one or more R.sup.21 groups.
[0426] In another embodiment of this invention R.sup.9 is
heteroaryl substituted with one or more R.sup.21 groups, and said
R.sup.21 groups are the same or different alkyl.
[0427] In another embodiment of this invention R.sup.9 is
heteroaryl substituted with one R.sup.21 group, and said R.sup.21
is alkyl.
[0428] In another embodiment of this invention R.sup.9 is
heteroaryl substituted with one R.sup.21 group, and said R.sup.21
is alkyl, and said alkyl is methyl.
[0429] In another embodiment of this invention R.sup.9 is and said
heteroaryl is imidazoyl.
[0430] In another embodiment of this invention R.sup.9 is
imidazolyl substituted with one or more R.sup.21 groups.
[0431] In another embodiment of this invention R.sup.9 is
imidazolyl substituted with one or more R.sup.21 groups, and said
R.sup.21 groups are the same or different alkyl.
[0432] In another embodiment of this invention R.sup.9 is
imidazolyl substituted with one R.sup.21 group, and said R.sup.21
is alkyl.
[0433] In another embodiment of this invention R.sup.9 is
imidazolyl substituted with one R.sup.21 group, and said R.sup.21
is alkyl, and said alkyl is methyl.
[0434] In another embodiment of this invention R.sup.10 is selected
from the group consisting of aryl and aryl substituted with one or
more R.sup.21 groups, and said R.sup.9 group is selected from the
group consisting of heteroaryl and heteroaryl substituted with one
or more R.sup.21 groups, wherein each R.sup.21 is independently
selected.
[0435] In another embodiment of this invention R.sup.10 is phenyl
substituted with one or more R.sup.21 groups, and said R.sup.9 is
imidazolyl substituted with one or more R.sup.21 groups, wherein
each R.sup.21 is independently selected.
[0436] In another embodiment of this invention R.sup.10 is phenyl
substituted with one R.sup.21 group, and said R.sup.9 is imidazolyl
substituted with one R.sup.21 group, wherein each R.sup.21 is
independently selected.
[0437] In another embodiment of this invention R.sup.10 is phenyl
substituted with one or more independently selected --OR.sup.15
groups, and said R.sup.9 is imidazolyl substituted with one or more
independently selected alkyl groups.
[0438] In another embodiment of this invention R.sup.10 is phenyl
substituted with one or more independently selected --OR.sup.15
groups, and said R.sup.9 is imidazolyl substituted with one or more
independently selected alkyl groups, and each R.sup.15 is the same
or different alkyl group.
[0439] In another embodiment of this invention R.sup.10 is phenyl
substituted with one --OR.sup.15 group, and said R.sup.9 is
imidazolyl substituted with one alkyl group.
[0440] In another embodiment of this invention R.sup.10 is phenyl
substituted with one --OR.sup.15 group, and said R.sup.9 is
imidazolyl substituted with one alkyl group, and R.sup.15 is alkyl,
and wherein the R.sup.15 alkyl group, and the alkyl group on said
imidazolyl are independently selected.
[0441] In another embodiment of this invention R.sup.10 is phenyl
substituted with one --OR.sup.15 group, and said R.sup.9 is
imidazolyl substituted with one methyl group, and R.sup.15 is
methyl, and wherein the R.sup.15 alkyl group, and the alkyl group
on said imidazolyl are independently selected.
[0442] In another embodiment of this invention the R.sup.9--
R.sup.10-moiety is:
##STR00039##
[0443] In another embodiment of this invention the
R.sup.9-R.sup.10-moiety is:
##STR00040##
[0444] In another embodiment of this invention the
R.sup.9-R.sup.10-moiety is:
##STR00041##
[0445] In another embodiment of this invention the
R.sup.9-R.sup.10-moiety is:
##STR00042##
[0446] In another embodiment of this invention the
R.sup.9-R.sup.10-moiety is:
##STR00043##
[0447] In another embodiment of this invention the
R.sup.9-R.sup.10-moiety is:
##STR00044##
[0448] In another embodiment of this invention R.sup.1 is an alkyl
group substituted with one or more independently selected R.sup.21
groups.
[0449] In another embodiment of this invention R.sup.1 is:
##STR00045##
wherein each R.sup.21 is independently selected, and each R.sup.21
is independently unsubstituted or substituted with one or more
independently selected R.sup.22 groups.
[0450] In another embodiment of this invention R.sup.1 is:
##STR00046##
wherein one R.sup.21 is an unsubstituted or substituted alkyl
group.
[0451] In another embodiment of this invention R.sup.1 is:
##STR00047##
wherein one R.sup.21 is an unsubstituted alkyl group.
[0452] In another embodiment of this invention R.sup.1 is:
##STR00048##
wherein one R.sup.21 is a substituted alkyl group.
[0453] In another embodiment of this invention R.sup.1 is:
##STR00049##
wherein one R.sup.21 is an unsubstituted or substituted alkyl
group, and the other R.sup.21 is an unsubstituted or substituted
aryl (e.g., phenyl) group.
[0454] In another embodiment of this invention R.sup.1 is:
##STR00050##
and R.sup.21 is unsubstituted or substituted with one or more
independently selected R.sup.22 groups.
[0455] In another embodiment of this invention R.sup.1 is:
##STR00051##
and R.sup.21 is unsubstituted aryl (e.g., phenyl) or aryl (e.g.,
phenyl) substituted with one or more independently selected
R.sup.22 groups.
[0456] In another embodiment of this invention R.sup.1 is an alkyl
group substituted with one R.sup.21 group.
[0457] In another embodiment of this invention R.sup.1 is an alkyl
group substituted with one R.sup.21 group, and said R.sup.21 group
is substituted with one or more independently selected R.sup.22
groups.
[0458] In another embodiment of this invention R.sup.1 is:
##STR00052##
wherein R.sup.21 is unsubstituted or substituted with one or more
independently selected R.sup.22 groups.
[0459] In another embodiment of this invention R.sup.1 is an alkyl
group substituted with one R.sup.21 group, and said R.sup.21 group
is an aryl group.
[0460] In another embodiment of this invention R.sup.1 is an alkyl
group substituted with one R.sup.21 group, and said R.sup.21 group
is an aryl group, said aryl is phenyl.
[0461] In another embodiment of this invention R.sup.1 is an ethyl
group substituted with one R.sup.21 group, and said R.sup.21 group
is an aryl group, said aryl is phenyl.
[0462] In another embodiment of this invention R.sup.1 is an methyl
group substituted with one R.sup.21 group, and said R.sup.21 group
is an aryl group, said aryl is phenyl.
[0463] In another embodiment of this invention R.sup.1 is an alkyl
group substituted with one R.sup.21 group, and said R.sup.21 group
is an aryl group, and said aryl group is substituted with one or
more independently selected R.sup.22 groups.
[0464] In another embodiment of this invention R.sup.1 is an alkyl
group substituted with one R.sup.21 group, and said R.sup.21 group
is an aryl group, and said aryl group is substituted with one or
more R.sup.22 groups, and each R.sup.22 group is the same or
different halo.
[0465] In another embodiment of this invention R.sup.1 is an alkyl
group substituted with one R.sup.21 group, and said R.sup.21 group
is an aryl group, and said aryl group is substituted with 1 to 3
R.sup.22 groups, and each R.sup.22 group is the same or different
halo.
[0466] In another embodiment of this invention R.sup.1 is an alkyl
group substituted with one R.sup.21 group, and said R.sup.21 group
is an aryl group, and said aryl group is substituted with one or
two R.sup.22 halo groups, and each R.sup.22 group is the same or
different halo,
[0467] In another embodiment of this invention R.sup.1 is an alkyl
group substituted with one R.sup.21 group, and said R.sup.21 group
is an aryl group, and said aryl group is substituted with one or
two R.sup.22 F groups.
[0468] In another embodiment of this invention R.sup.1 is an alkyl
group substituted with one R.sup.21 group, and said R.sup.21 group
is phenyl, and said phenyl is substituted with one or more
independently selected R.sup.22 groups.
[0469] In another embodiment of this invention R.sup.1 is an alkyl
group substituted with one R.sup.21 group, and said R.sup.21 group
is phenyl, and said phenyl is substituted with one or more R.sup.22
groups, and each R.sup.22 group is the same or different halo.
[0470] In another embodiment of this invention R.sup.1 is an alkyl
group substituted with one R.sup.21 group, and said R.sup.21 group
is phenyl, and said phenyl is substituted with one or two R.sup.22
halo groups, and each R.sup.22 group is the same or different
halo.
[0471] In another embodiment of this invention R.sup.1 is an alkyl
group substituted with one R.sup.21 group, and said R.sup.21 group
is phenyl, and said phenyl is substituted with one or two R.sup.22
F groups.
[0472] In another embodiment of this invention R.sup.1 is an alkyl
group substituted with one R.sup.21 group, and said R.sup.21 group
is phenyl, and said phenyl is substituted with three R.sup.22 halo
groups, and each R.sup.22 group is the same or different halo.
[0473] In another embodiment of this invention R.sup.1 is an alkyl
group substituted with one R.sup.21 group, and said R.sup.21 group
is phenyl, and said phenyl is substituted with three R.sup.22 F
groups.
[0474] In another embodiment of this invention R.sup.1 is an ethyl
group substituted with one R.sup.21 group, and said R.sup.21 group
is an aryl group, and said aryl group is substituted with one or
more independently selected R.sup.22 groups.
[0475] In another embodiment of this invention R.sup.1 is a methyl
group substituted with one R.sup.21 group, and said R.sup.21 group
is an aryl group, and said aryl group is substituted with one or
more independently selected R.sup.22 groups.
[0476] In another embodiment of this invention R.sup.1 is an ethyl
group substituted with one R.sup.21 group, and said R.sup.21 is
phenyl, and said phenyl is substituted with one or more
independently selected R.sup.22 groups.
[0477] In another embodiment of this invention R.sup.1 is a methyl
group substituted with one R.sup.21 group, and said R.sup.21 group
is phenyl, and said phenyl is substituted with one or more
independently selected R.sup.22 groups.
[0478] In another embodiment of this invention R.sup.1 is an ethyl
group substituted with one R.sup.21 group, and said R.sup.21 group
is phenyl, and said phenyl is substituted with one or two R.sup.22
halo groups, and each R.sup.22 group is the same or different
halo.
[0479] In another embodiment of this invention R.sup.1 is a methyl
group substituted with one R.sup.21 group, and said R.sup.21 group
is phenyl, and said phenyl is substituted with one or two R.sup.22
halo groups, and each R.sup.22 group is the same or different
halo.
[0480] In another embodiment of this invention R.sup.1 is an ethyl
group substituted with one R.sup.21 group, and said R.sup.21 group
is phenyl, and said phenyl is substituted with one or two R.sup.22
F groups.
[0481] In another embodiment of this invention R.sup.1 is a methyl
group substituted with one R.sup.21 group, and said R.sup.21 group
is phenyl, and said phenyl is substituted with one or two R.sup.22
F groups.
[0482] In another embodiment of this invention R.sup.1 is an ethyl
group substituted with one R.sup.21 group, and said R.sup.21 group
is phenyl, and said phenyl is substituted with one R.sup.22 halo
group.
[0483] In another embodiment of this invention R.sup.1 is a methyl
group substituted with one R.sup.21 group, and said R.sup.21 group
is phenyl, and said phenyl is substituted with one R.sup.22 halo
group.
[0484] In another embodiment of this invention R.sup.1 is an ethyl
group substituted with one R.sup.21 group, and said R.sup.21 group
is phenyl, and said phenyl is substituted with one R.sup.22 F
group.
[0485] In another embodiment of this invention R.sup.1 is a methyl
group substituted with one R.sup.21 group, and said R.sup.21 group
is phenyl, and said phenyl is substituted with one R.sup.22 F
group.
[0486] In another embodiment of this invention R.sup.1 is an ethyl
group substituted with one R.sup.21 group, and said R.sup.21 group
is phenyl, and said phenyl is substituted with three independently
selected R.sup.22 halo groups.
[0487] In another embodiment of this invention R.sup.1 is a methyl
group substituted with one R.sup.21 group, and said R.sup.21 group
is phenyl, and said phenyl is substituted with three R.sup.22
independently selected halo groups.
[0488] In another embodiment of this invention R.sup.1 an ethyl
group substituted with one R.sup.21 group, and said R.sup.21 group
is phenyl, and said phenyl is substituted with three R.sup.22 F
groups.
[0489] In another embodiment of this invention R.sup.1 is a methyl
group substituted with one R.sup.21 group, and said R.sup.21 group
is phenyl, and said phenyl is substituted with three R.sup.22 F
groups.
[0490] In another embodiment of this invention R.sup.1 is selected
from the group consisting of:
##STR00053##
[0491] In another embodiment of this invention R.sup.1 is an alkyl
group (and in one example R.sup.1 is methyl, and in another example
R.sup.1 is ethyl) substituted with a group selected from the group
consisting of:
##STR00054## ##STR00055##
[0492] In another embodiment of this invention R.sup.1 is an alkyl
group (and in one example R.sup.1 is methyl, and in another example
R.sup.1 is ethyl) substituted with a group selected from the group
consisting of:
##STR00056##
[0493] In another embodiment of this invention R.sup.1 is an alkyl
group (and in one example R.sup.1 is methyl, and in another example
R.sup.1 is ethyl) substituted with
##STR00057##
[0494] In another embodiment of this invention R.sup.1 is an alkyl
group (and in one example R.sup.1 is methyl, and in another example
R.sup.1 is ethyl) substituted with
##STR00058##
[0495] In another embodiment of this invention R.sup.1 is an alkyl
group (and in one example R.sup.1 is methyl; and in another example
R.sup.1 is ethyl) substituted with
##STR00059##
[0496] In another embodiment of this invention R.sup.1 is an alkyl
group (and in one example R.sup.1 is methyl, and in another example
R.sup.1 is ethyl) substituted with
##STR00060##
[0497] In another embodiment of this invention R.sup.1 is an alkyl
group (and in one example R.sup.1 is methyl, and in another example
R.sup.1 is ethyl) substituted with
##STR00061##
[0498] In another embodiment of this invention R.sup.1 is an alkyl
group (and in one example R.sup.1 is methyl, and in another example
R.sup.1 is ethyl) substituted with
##STR00062##
[0499] In another embodiment of this invention R.sup.1 is an alkyl
group (and in one example R.sup.1 is methyl, and in another example
R.sup.1 is ethyl) substituted with
##STR00063##
[0500] In another embodiment of this invention R.sup.1 is an alkyl
group (and in one example R.sup.1 is methyl, and in another example
R.sup.1 is ethyl) substituted with
##STR00064##
[0501] In another embodiment of this invention R.sup.1 is an alkyl
group (and in one example R.sup.1 is methyl, and in another example
R.sup.1 is ethyl) substituted with
##STR00065##
[0502] In another embodiment of this invention R.sup.1 is an alkyl
group (and in one example R.sup.1 is methyl, and in another example
R.sup.1 is ethyl) substituted with
##STR00066##
[0503] In another embodiment of this invention R.sup.1 is an alkyl
group (and in one example R.sup.1 is methyl, and in another example
R.sup.1 is ethyl) substituted with
##STR00067##
[0504] In another embodiment of this invention R.sup.1 is an alkyl
group (and in one example R.sup.1 is methyl, and in another example
R.sup.1 is ethyl) substituted with
##STR00068##
[0505] In another embodiment of this invention R.sup.1 is an alkyl
group (and in one example R.sup.1 is methyl, and in another example
R.sup.1 is ethyl) substituted with
##STR00069##
[0506] In another embodiment of this invention R.sup.1 is an alkyl
group (and in one example R.sup.1 is methyl, and in another example
R.sup.1 is ethyl) substituted with
##STR00070##
[0507] In another embodiment of this invention R.sup.1 is an alkyl
group (and in one example R.sup.1 is methyl, and in another example
R.sup.1 is ethyl) substituted with
##STR00071##
[0508] In another embodiment of this invention R.sup.1 is an alkyl
group (and in one example R.sup.1 is methyl, and in another example
R.sup.1 is ethyl) substituted with
##STR00072##
[0509] In another embodiment of this invention R.sup.1 is an alkyl
group (and in one example R.sup.1 is methyl, and in another example
R.sup.1 is ethyl) substituted with
##STR00073##
[0510] In another embodiment of this invention R.sup.1 is an alkyl
group (and in one example R.sup.1 is methyl, and in another example
R.sup.1 is ethyl) substituted with
##STR00074##
[0511] In another embodiment of this invention R.sup.1 is an alkyl
group (and in one example R.sup.1 is methyl, and in another example
R.sup.1 is ethyl) substituted with
##STR00075##
[0512] In another embodiment of this invention R.sup.1 is an alkyl
group (and in one example R.sup.1 is methyl, and in another example
R.sup.1 is ethyl) substituted with
##STR00076##
[0513] In another embodiment of this invention R.sup.1 is an alkyl
group (and in one example R.sup.1 is methyl, and in another example
R.sup.1 is ethyl) substituted with
##STR00077##
[0514] In another embodiment of this invention R.sup.1 is an alkyl
group (and in one example R.sup.1 is methyl, and in another example
R.sup.1 is ethyl) substituted with
##STR00078##
[0515] In another embodiment of this invention R.sup.1 is an alkyl
group (and in one example R.sup.1 is methyl, and in another example
R.sup.1 is ethyl) substituted with
##STR00079##
[0516] In another embodiment of this invention R.sup.1 is an alkyl
group (and in one example R.sup.1 is methyl, and in another example
R.sup.1 is ethyl) substituted with
##STR00080##
[0517] In another embodiment of this invention R.sup.1 is an alkyl
group (and in one example R.sup.1 is methyl, and in another example
R.sup.1 is ethyl) substituted with a phenyl that is substituted
with 1-3 halos independently selected from the group consisting of
F and Cl. In one example said phenyl is substituted with one F and
one Cl.
[0518] In another embodiment of this invention R.sup.1 is an alkyl
group (and in one example R.sup.1 is methyl, and in another example
R.sup.1 is ethyl) substituted with an aryl (e.g., phenyl) that is
substituted with 1 to 3 independently selected R.sup.21 moieties
wherein at least one R.sup.21 moiety is selected from the group
consisting of --SF.sub.5, --OSF.sub.5 and --Si(R.sup.15A).sub.3
(and in one example each R.sup.15A is the same or different alkyl,
and in another example the --Si(R.sup.24).sub.3 group is
--Si(CH.sub.3).sub.3 or --Si(CH.sub.2CH.sub.3).sub.2CH.sub.3, and
in another example the --Si(R.sup.24).sub.3 group is
--Si(CH.sub.3).sub.3).
[0519] In another embodiment of this invention R.sup.1 is an alkyl
group (and in one example R.sup.1 is methyl, and in another example
R.sup.1 is ethyl) substituted with an aryl (e.g., phenyl) that is
substituted with 1 to 3 independently selected R.sup.21 moieties
wherein at least one R.sup.21 moiety is selected from the group
consisting of --SF.sub.5 and --OSF.sub.5.
[0520] In another embodiment of this invention R.sup.1 is an alkyl
group (and in one example R.sup.1 is methyl, and in another example
R.sup.1 is ethyl) substituted with an aryl (e.g., phenyl) that is
substituted with 1 to 3 R.sup.21 moieties independently selected
from the group consisting of: halo (e.g., F), --SF.sub.5,
--OSF.sub.5 and --Si(R.sup.15A).sub.3 (and in one example each
R.sup.15A is the same or different alkyl, and in another example
the --Si(R.sup.15A).sub.3 group is --Si(CH.sub.3).sub.3 or
--Si(CH.sub.2CH.sub.3).sub.2CH.sub.3, and in another example the
--Si(R.sup.15A).sub.3 group is --Si(CH.sub.3).sub.3), and wherein
at least one R.sup.21 moiety is selected from the group consisting
of --SF.sub.5, --OSF.sub.5 and --Si(R.sup.15A).sub.3 (and in one
example each R.sup.15A is the same or different alkyl, and in
another example the --Si(R.sup.15A).sub.3 group is
--Si(CH.sub.3).sub.3 or --Si(CH.sub.2CH.sub.3).sub.2CH.sub.3, and
in another example the --Si(R.sup.24).sub.3 group is
--Si(CH.sub.3).sub.3).
[0521] In another embodiment of this invention R.sup.1 is an alkyl
group (and in one example R.sup.1 is methyl, and in another example
R.sup.1 is ethyl) substituted with an aryl (e.g., phenyl) that is
substituted with 1 to 3 R.sup.21 moieties independently selected
from the group consisting of: halo (e.g., F), --SF.sub.5 and
--OSF.sub.5, and wherein at least one R.sup.21 moiety is selected
from the group consisting of --SF.sub.5 and --OSF.sub.5.
[0522] In another embodiment of this invention R.sup.1 is an alkyl
group (and in one example R.sup.1 is methyl, and in another example
R.sup.1 is ethyl) substituted with an aryl (e.g., phenyl) that is
substituted with 1 to 3 independently selected R.sup.21 moieties
wherein at least one R.sup.21 moiety is selected from the group
consisting of --SF.sub.5, --OSF.sub.5 and --Si(R.sup.15A).sub.3
(and in one example each R.sup.15A is the same or different alkyl,
and in another example the --Si(R.sup.15A).sub.3 group is
--Si(CH.sub.3).sub.3 or --Si(CH.sub.2CH.sub.3).sub.2CH.sub.3, and
in another example the --Si(R.sup.15A).sub.3 group is
--Si(CH.sub.3).sub.3).
[0523] In another embodiment of this invention R.sup.1 is an alkyl
group (and in one example R.sup.1 is methyl, and in another example
R.sup.1 is ethyl) substituted with a phenyl that is substituted
with 1-3 R.sup.21 groups independently selected from the group
consisting of halos, --SF.sub.5 and --OSF.sub.5, wherein at least
one R.sup.21 group is --SF.sub.5 or --OSF.sub.5.
[0524] In another embodiment of this invention R.sup.1 is an alkyl
group (and in one example R.sup.1 is methyl, and in another example
R.sup.1 is ethyl) substituted with a phenyl that is substituted
with 1-3 R.sup.21 groups independently selected from the group
consisting of halos, --SF.sub.5 and --OSF.sub.5, wherein at least
one R.sup.21 group is --SF.sub.5 or --OSF.sub.5.
[0525] In another embodiment of this invention R.sup.1 is an alkyl
group (and in one example R.sup.1 is methyl, and in another example
R.sup.1 is ethyl) substituted with a phenyl that is substituted
with 1-3 R.sup.21 groups independently selected from the group
consisting of F, Cl, --SF.sub.5 and --OSF.sub.5.
[0526] In another embodiment of this invention R.sup.1 is an alkyl
group (and in one example R.sup.1 is methyl, and in another example
R.sup.1 is ethyl) substituted with a phenyl that is substituted
with 1-3 R.sup.21 groups independently selected from the group
consisting of --SF.sub.5 and --OSF.sub.5.
[0527] In another embodiment of this invention R.sup.1 is an alkyl
group (and in one example R.sup.1 is methyl, and in another example
R.sup.1 is ethyl) substituted with a phenyl substituted with 1-3
R.sup.21 groups independently selected from the group consisting of
F, --SF.sub.5 and --OSF.sub.5, wherein at least one R.sup.21 group
is --SF.sub.5 or --OSF.sub.5.
[0528] In another embodiment of this invention R.sup.1 is an alkyl
group (and in one example R.sup.1 is methyl, and in another example
R.sup.1 is ethyl) substituted with a phenyl that is substituted
with one --SF.sub.5 group.
[0529] In another embodiment of this invention R.sup.1 is an alkyl
group (and in one example R.sup.1 is methyl, and in another example
R.sup.1 is ethyl) substituted with a phenyl that is substituted
with two --SF.sub.5 groups.
[0530] In another embodiment of this invention R.sup.1 is an alkyl
group (and in one example R.sup.1 is methyl, and in another example
R.sup.1 is ethyl) substituted with a phenyl that is substituted
with three --SF.sub.5 groups.
[0531] In another embodiment of this invention R.sup.1 is an alkyl
group (and in one example R.sup.1 is methyl, and in another example
R.sup.1 is ethyl) substituted with a phenyl that is substituted
with one --OSF.sub.5 group.
[0532] In another embodiment of this invention R.sup.1 is an alkyl
group (and in one example R.sup.1 is methyl, and in another example
R.sup.1 is ethyl) substituted with a phenyl that is substituted
with two --OSF.sub.5 groups.
[0533] In another embodiment of this invention R.sup.1 is an alkyl
group (and in one example R.sup.1 is methyl, and in another example
R.sup.1 is ethyl) substituted with a phenyl that is substituted
with three --OSF.sub.5 groups.
[0534] In another embodiment of this invention R.sup.1 is an alkyl
group (and in one example R.sup.1 is methyl, and in another example
R.sup.1 is ethyl) substituted with a phenyl that is substituted
with 1 F.
[0535] In another embodiment of this invention R.sup.1 is an alkyl
group (and in one example R.sup.1 is methyl, and in another example
R.sup.1 is ethyl) substituted with a phenyl that is substituted
with 1 F, and also substituted with 1 to 2 groups independently
selected from the group consisting of --SF.sub.5 and
--OSF.sub.5.
[0536] In another embodiment of this invention R.sup.1 is an alkyl
group (and in one example R.sup.1 is methyl, and in another example
R.sup.1 is ethyl) substituted with a phenyl that is substituted
with 2 F.
[0537] In another embodiment of this invention R.sup.1 is an alkyl
group (and in one example R.sup.1 is methyl, and in another example
R.sup.1 is ethyl) substituted with a phenyl that is substituted
with 3F.
[0538] In another embodiment of this invention R.sup.1 is an
unsubstituted or substituted aryl (e.g., phenyl) group.
[0539] In another embodiment of this invention R.sup.1 is an
unsubstituted aryl (e.g., phenyl) or aryl (e.g., phenyl)
substituted with one or more independently selected R.sup.21
groups.
[0540] In another embodiment of this invention R.sup.1 is an aryl
group.
[0541] In another embodiment of this invention R.sup.1 is an aryl
group, and said aryl group is substituted with one or more
independently selected R.sup.21 groups.
[0542] In another embodiment of this invention R.sup.1 is an aryl
group, and said aryl group is substituted with 1 to 3 independently
selected R.sup.21 groups.
[0543] In another embodiment of this invention R.sup.1 is an aryl
group, and said aryl group is substituted with one or more R.sup.21
groups, and each R.sup.21 group is the same or different halo.
[0544] In another embodiment of this invention R.sup.1 is an aryl
group, and said aryl group is substituted with 1 to 3 R.sup.21
groups, and each R.sup.21 group is the same or different halo.
[0545] In another embodiment of this invention R.sup.1 is an aryl
group, and said aryl group is substituted with three R.sup.21 halo
groups, and each R.sup.21 group is the same or different halo.
[0546] In another embodiment of this invention R.sup.1 is an aryl
group, and said aryl group is substituted with two R.sup.21 halo
groups, and each R.sup.21 group is the same or different halo.
[0547] In another embodiment of this invention R.sup.1 is an aryl
group, and said aryl group is substituted with one R.sup.21 halo
group.
[0548] In another embodiment of this invention R.sup.1 is an aryl
group, and said aryl group is substituted with one R.sup.21 halo
groups, and each R.sup.21 group is the same or different halo.
[0549] In another embodiment of this invention R.sup.1 is an aryl
group, and said aryl group is substituted with one F (i.e., said
aryl is substituted with one R.sup.21 group, and said R.sup.21
group is halo, and said halo is F).
[0550] In another embodiment of this invention R.sup.1 is an aryl
group, and said aryl group is substituted with two F atoms (i.e.,
said aryl is substituted with two R.sup.21 groups, and said
R.sup.21 groups are halo, and said halo is F).
[0551] In another embodiment of this invention R.sup.1 is an aryl
group, and said aryl group is substituted with three F atoms (i.e.,
said aryl is substituted with three R.sup.21 groups, and said
R.sup.21 groups are halo, and said halo is F).
[0552] In another embodiment of this invention R.sup.1 is
phenyl.
[0553] In another embodiment of this invention R.sup.1 is phenyl,
and said phenyl is substituted with one or more independently
selected R.sup.21 groups.
[0554] In another embodiment of this invention R.sup.1 is phenyl,
and said phenyl is substituted with 1 to 3 independently selected
R.sup.21 groups.
[0555] In another embodiment of this invention R.sup.1 is a phenyl,
and said phenyl is substituted with one or more R.sup.21 groups,
and each R.sup.21 group is the same or different halo.
[0556] In another embodiment of this invention R.sup.1 is phenyl,
and said phenyl is substituted with 1 to 3 R.sup.21 groups, and
each R.sup.21 group is the same or different halo.
[0557] In another embodiment of this invention R.sup.1 is phenyl,
and said phenyl is substituted with three R.sup.21 halo groups, and
each R.sup.21 group is the same or different halo.
[0558] In another embodiment of this invention R.sup.1 is phenyl,
and said phenyl is substituted with two R.sup.21 halo groups, and
each R.sup.21 group is the same or different halo.
[0559] In another embodiment of this invention R.sup.1 is phenyl,
and said phenyl is substituted with one R.sup.21 halo group.
[0560] In another embodiment of this invention R.sup.1 is phenyl,
and said phenyl is substituted with one R.sup.21 halo group.
[0561] In another embodiment of this invention R.sup.1 is phenyl,
and said phenyl is substituted with one F (i.e., said aryl is
substituted with one R.sup.21 group, and said R.sup.21 group is
halo, and said halo is F).
[0562] In another embodiment of this invention R.sup.1 is phenyl,
and said phenyl is substituted with two F atoms (i.e., said aryl is
substituted with two R.sup.21 groups, and said R.sup.21 groups are
halo, and said halo is F).
[0563] In another embodiment of this invention R.sup.1 is phenyl,
and said phenyl is substituted with three F atoms (i.e., said aryl
is substituted with three R.sup.21 groups, and said R.sup.21 groups
are halo, and said halo is F).
[0564] In another embodiment of this invention R.sup.1 is selected
from the group consisting of:
##STR00081## ##STR00082##
[0565] In another embodiment of this invention R.sup.1 is selected
from the group consisting of:
##STR00083##
[0566] In another embodiment of this invention R.sup.1 is selected
from the group consisting of:
##STR00084##
[0567] In another embodiment of this invention R.sup.1 is selected
from the group consisting of:
##STR00085##
##STR00086##
[0568] In another embodiment of this invention R.sup.1 is:
##STR00087##
[0569] In another embodiment of this invention R.sup.1 is:
##STR00088##
[0570] In another embodiment of this invention R.sup.1A is:
##STR00089##
[0571] In another embodiment of this invention R.sup.1 is:
##STR00090##
[0572] In another embodiment of this invention R.sup.1A is:
##STR00091##
[0573] In another embodiment of this invention R.sup.1 is:
##STR00092##
[0574] In another embodiment of this invention R.sup.1A is:
##STR00093##
[0575] In another embodiment of this invention R.sup.1 is:
##STR00094##
[0576] In another embodiment of this invention R.sup.1 is:
##STR00095##
[0577] In another embodiment of this invention R.sup.1 is:
##STR00096##
[0578] In another embodiment of this invention R.sup.1A is:
##STR00097##
[0579] In another embodiment of this invention R.sup.1 is:
##STR00098##
[0580] In another embodiment of this invention R.sup.1 is:
##STR00099##
[0581] In another embodiment of this invention R.sup.1 is:
##STR00100##
[0582] In another embodiment of this invention R.sup.1 is:
##STR00101##
[0583] In another embodiment of is invention R.sup.1 is:
##STR00102##
[0584] In another embodiment of this invention. R.sup.1 is
##STR00103##
[0585] In another embodiment of this invention R.sup.1 is:
##STR00104##
[0586] In another embodiment of this invention R.sup.1A is:
##STR00105##
[0587] In another embodiment of this invention R.sup.1 is:
##STR00106##
[0588] In another embodiment of this invention R.sup.1 is:
##STR00107##
[0589] In another embodiment of this invention R.sup.1 is:
##STR00108##
[0590] In another embodiment of this invention R.sup.1 is:
##STR00109##
[0591] In another embodiment, R.sup.1 is phenyl substituted with
1-3 halos independently selected from the group consisting of F and
Cl. In one example said phenyl is substituted with one F and one
Cl.
[0592] In another embodiment R.sup.1 is aryl (e.g., phenyl)
substituted with 1 to 3 independently selected R.sup.21 moieties
wherein at least one R.sup.21 moiety is selected from the group
consisting of --SF.sub.5, --OSF.sub.5 and --Si(R.sup.15A).sub.3
(and in one example each R.sup.15A is the same or different alkyl,
and in another example the --Si(R.sup.24).sub.3 group is
--Si(CH.sub.3).sub.3 or --Si(CH.sub.2CH.sub.3).sub.2CH.sub.3, and
in another example the --Si(R.sup.24).sub.3 group is
--Si(CH.sub.3).sub.3).
[0593] In another embodiment R.sup.1 is aryl (e.g., phenyl)
substituted with 1 to 3 independently selected R.sup.21 moieties
wherein at least one R.sup.21 moiety is selected from the group
consisting of --SF.sub.5 and --OSF.sub.5.
[0594] In another embodiment R.sup.1 is aryl (e.g., phenyl)
substituted with 1 to 3 R.sup.21 moieties independently selected
from the group consisting of: halo (e.g., F), --SF.sub.5,
--OSF.sub.5 and --Si(R.sup.15A).sub.3 (and in one example each
R.sup.15A is the same or different alkyl, and in another example
the --Si(R.sup.15A).sub.3 group is --Si(CH.sub.3).sub.3 or
--Si(CH.sub.2CH.sub.3).sub.2CH.sub.3, and in another example the
--Si(R.sup.15A).sub.3 group is --Si(CH.sub.3).sub.3), and wherein
at least one R.sup.21 moiety is selected from the group consisting
of --SF.sub.5, --OSF.sub.5 and --Si(R.sup.15A).sub.3 (and in one
example each R.sup.15A is the same or different alkyl, and in
another example the --Si(R.sup.15A).sub.3 group is
--Si(CH.sub.3).sub.3 or --Si(CH.sub.2CH.sub.3).sub.2CH.sub.3, and
in another example the --Si(R.sup.24).sub.3 group is
--Si(CH.sub.3).sub.3).
[0595] In another embodiment R.sup.1 is aryl (e.g., phenyl)
substituted with 1 to 3 R.sup.21 moieties independently selected
from the group consisting of: halo (e.g., F), --SF.sub.5 and
--OSF.sub.5, and wherein at least one R.sup.21 moiety is selected
from the group consisting of --SF.sub.5 and --OSF.sub.5.
[0596] In another embodiment R.sup.1 is aryl (e.g., phenyl)
substituted with 1 to 3 independently selected R.sup.21 moieties
wherein at least one R.sup.21 moiety is selected from the group
consisting of --SF.sub.5, --OSF.sub.5 and --Si(R.sup.15A).sub.3
(and in one example each R.sup.15A is the same or different alkyl,
and in another example the --Si(R.sup.15A).sub.3 group is
--Si(CH.sub.3).sub.3 or --Si(CH.sub.2CH.sub.3).sub.2CH.sub.3, and
in another example the --Si(R.sup.15A).sub.3 group is
--Si(CH.sub.3).sub.3)
[0597] In another embodiment, R.sup.1 is phenyl substituted with
1-3 R.sup.21 groups independently selected from the group
consisting of halos, --SF.sub.5 and --OSF.sub.5, wherein at least
one R.sup.21 group is --SF.sub.5 or --OSF.sub.5.
[0598] In another embodiment, R.sup.1 is phenyl substituted with
1-3 R.sup.21 groups independently selected from the group
consisting of halos, --SF.sub.5 and --OSF.sub.5, wherein at least
one R.sup.21 group is --SF.sub.5 or --OSF.sub.5.
[0599] In another embodiment, R.sup.1 is phenyl substituted with
1-3 R.sup.21 groups independently selected from the group
consisting of F, Cl, --SF.sub.5 and --OSF.sub.5.
[0600] In another embodiment, R.sup.1 is phenyl substituted with
1-3 R.sup.21 groups independently selected from the group
consisting of --SF.sub.5 and --OSF.sub.5.
[0601] In another embodiment, R.sup.1 is phenyl substituted with
1-3 R.sup.21 groups independently selected from the group
consisting of F, --SF.sub.5 and --OSF.sub.5, wherein at least one
R.sup.21 group is --SF.sub.5 or --OSF.sub.5.
[0602] In another embodiment, R.sup.1 is phenyl substituted with
one --SF.sub.5 group.
[0603] In another embodiment, R.sup.1 is phenyl substituted with
two --SF.sub.5 groups.
[0604] In another embodiment, R.sup.1 is phenyl substituted with
three --SF.sub.5 groups.
[0605] In another embodiment, R.sup.1 is phenyl substituted with
one --OSF.sub.5 group.
[0606] In another embodiment, R.sup.1 is phenyl substituted with
two --OSF.sub.5 groups.
[0607] In another embodiment, R.sup.1 is phenyl substituted with
three --OSF.sub.5 groups.
[0608] In another embodiment, R.sup.1 is phenyl substituted with 1
F.
[0609] In another embodiment, R.sup.1 is phenyl substituted with 1
F, and also substituted with 1 to 2 groups independently selected
from the group consisting of --SF.sub.5 and --OSF.sub.5.
[0610] In another embodiment R.sup.1 is phenyl substituted with 2
F.
[0611] In another embodiment R.sup.1 is phenyl substituted with
3F.
[0612] In another embodiment of this invention R.sup.10 is selected
from the group consisting of aryl and aryl substituted with one or
more R.sup.21 groups, and said R.sup.9 group is selected from the
group consisting of heteroaryl and heteroaryl substituted with one
or more R.sup.21 groups, and wherein each R.sup.21 is independently
selected.
[0613] In another embodiment of this invention: (a) R.sup.1 is an
alkyl group substituted with one R.sup.21 group, or (b) R.sup.1 is
an alkyl group substituted with one R.sup.21 group, and said
R.sup.21 group is substituted with one or more independently
selected R.sup.22 groups, and (c) R.sup.10 is selected from the
group consisting of aryl and aryl substituted with one or more
independently selected R.sup.21 groups, and (d) R.sup.9 is selected
from the group consisting of heteroaryl and heteroaryl substituted
with one or more independently selected R.sup.21 groups.
[0614] In another embodiment of this invention: (a) R.sup.1 is an
alkyl group substituted with one phenyl group, or (b) R.sup.1 is an
alkyl group substituted with one phenyl group, and said phenyl
group is substituted with one or more independently selected
R.sup.22 groups, and (c) R.sup.10 is selected from the group
consisting of phenyl and phenyl substituted with one or more
independently selected R.sup.21 groups, and (d) R.sup.9 is selected
from the group consisting of imidazolyl and imidazolyl substituted
with one or more independently selected R.sup.21 groups.
[0615] In another embodiment of this invention: (a) R.sup.1 is a
methyl or ethyl group substituted with one phenyl, or (b) R.sup.1
is an methyl or alkyl group substituted with one phenyl, and said
phenyl is substituted with one or more independently selected
halos, and (c) R.sup.10 is selected from the group consisting of
phenyl and phenyl substituted with one or more independently
selected --OR.sup.15 groups, and (d) R.sup.9 is selected from the
group consisting of imidazolyl and imidazolyl substituted with one
or more independently selected alkyl groups groups.
[0616] In another embodiment of this invention: (a) R.sup.1 is a
methyl or ethyl group substituted with one phenyl, or (b) R.sup.1
is an methyl or alkyl group substituted with one phenyl, and said
phenyl is substituted with one or two independently selected halos,
and (c) R.sup.10 is selected from the group consisting of phenyl
and phenyl substituted with one or two independently selected
--OR.sup.15 groups, wherein R.sup.15 is alkyl, and (d) R.sup.9 is
selected from the group consisting of imidazolyl and imidazolyl
substituted with one or two independently selected alkyl groups
groups.
[0617] In another embodiment of this invention: (a) R.sup.1 is a
methyl or ethyl group substituted with one phenyl, or (b) R.sup.1
is an methyl or alkyl group substituted with one phenyl, and said
phenyl is substituted with one or two F, and (c) R.sup.10 is
selected from the group consisting of phenyl and phenyl substituted
with one or two independently selected --OR.sup.15 groups, wherein
R.sup.15 is methyl and (d) R.sup.9 is selected from the group
consisting of imidazolyl and imidazolyl substituted with one or two
independently selected methyl groups groups.
[0618] In another embodiment of this invention: (a) R.sup.1 is a
methyl or ethyl group substituted with one phenyl, or (b) R.sup.1
is an methyl or alkyl group substituted with one phenyl; and said
phenyl is substituted with one or two F, and (c) R.sup.10 is phenyl
substituted with one --OR.sup.15 group, wherein R.sup.15 is methyl,
and (d) R.sup.9 is selected from the group consisting of imidazolyl
and imidazolyl substituted with one methyl group.
[0619] In another embodiment of this invention R.sup.1 is selected
from the group consisting of:
##STR00110##
and wherein the R.sup.9-R.sup.10-moiety is:
##STR00111##
[0620] In another embodiment of this invention R is selected from
the group consisting of:
##STR00112##
and wherein the R.sup.9-R.sup.10-moiety is:
##STR00113##
[0621] In another embodiment of this invention R.sup.1 is selected
from the group consisting of:
##STR00114##
wherein the R.sup.9-R.sup.10-moiety is:
##STR00115##
[0622] In another embodiment of this invention R.sup.1 is selected
from the group consisting of:
##STR00116##
wherein the R.sup.9-R.sup.10-moiety is:
##STR00117##
[0623] In another embodiment of this invention R.sup.1 is selected
from the group consisting of:
##STR00118##
wherein the R.sup.9-R.sup.10-moiety is:
##STR00119##
[0624] In another embodiment of this invention: (a) R.sup.1 is a
methyl or ethyl group substituted with one phenyl, or (b) R.sup.1
is an methyl or alkyl group substituted with one phenyl, and said
phenyl is substituted with 1 to 3 independently selected halos, and
(c) R.sup.10 is selected from the group consisting of phenyl and
phenyl substituted with one or two independently selected
--OR.sup.15 groups, wherein R.sup.15 is alkyl, and (d) R.sup.9 is
selected from the group consisting of imidazolyl and imidazolyl
substituted with one or two independently selected alkyl groups
groups.
[0625] In another embodiment of this invention: (a) R.sup.1 is a
methyl or ethyl group substituted with one phenyl, or (b) R.sup.1
is an methyl or alkyl group substituted with one phenyl, and said
phenyl is substituted with 1 to 3 independently selected halos, and
(c) R.sup.10 is selected from the group consisting of phenyl and
phenyl substituted with one or two independently selected
--OR.sup.15 groups, wherein R.sup.15 is alkyl, and (d) R.sup.9 is
selected from the group consisting of imidazolyl and imidazolyl
substituted with one or two independently selected alkyl groups
groups, and (e) G.sup.5 is selected from the group consisting of
--N.dbd., --NH--, --O-- and --S--.
[0626] In another embodiment of this invention: (a) R.sup.1 is a
methyl or ethyl group substituted with one phenyl, or (b) R.sup.1
is an methyl or alkyl group substituted with one phenyl, and said
phenyl is substituted with 1 to 3 independently selected halos, and
(c) R.sup.10 is selected from the group consisting of phenyl and
phenyl substituted with one or two independently selected
--OR.sup.15 groups, wherein R.sup.15 is alkyl, and (d) R.sup.9 is
selected from the group consisting of imidazolyl and imidazolyl
substituted with one or two independently selected alkyl groups
groups, and (e) G.sup.5 is selected from the group consisting of
--N.dbd., --NH--, --O-- and --S--, and (f) G.sup.6 is C or CH.
[0627] In another embodiment of this invention: (a) R.sup.1 is a
methyl or ethyl group substituted with one phenyl, or (b) R.sup.1
is an methyl or alkyl group substituted with one phenyl, and said
phenyl is substituted with 1 to 3 F, and (c) R.sup.10 is selected
from the group consisting of phenyl and phenyl substituted with one
or two independently selected --OR.sup.15 groups, wherein R.sup.15
is alkyl, and (d) R.sup.9 is selected from the group consisting of
imidazolyl and imidazolyl substituted with one or two independently
selected alkyl groups groups.
[0628] In another embodiment of this invention: (a) R.sup.1 is a
methyl or ethyl group substituted with one phenyl, or (b) R.sup.1
is an methyl or alkyl group substituted with one phenyl, and said
phenyl is substituted with 1 to 3 F, and (c) R.sup.10 is selected
from the group consisting of phenyl and phenyl substituted with one
or two independently selected --OR.sup.15 groups, wherein R.sup.15
is alkyl, and (d) R.sup.9 is selected from the group consisting of
imidazolyl and imidazolyl substituted with one or two independently
selected alkyl groups groups, and (e) G.sup.5 is selected from the
group consisting of --N.dbd., --NH--, --O-- and --S--.
[0629] In another embodiment of this invention: (a) R.sup.1 is a
methyl or ethyl group substituted with one phenyl, or (b) R.sup.1
is an methyl or alkyl group substituted with one phenyl, and said
phenyl is substituted with 1 to 3 F, and (c) R.sup.10 is selected
from the group consisting of phenyl and phenyl substituted with one
or two independently selected --OR.sup.15 groups, wherein R.sup.15
is alkyl, and (d) R.sup.9 is selected from the group consisting of
imidazolyl and imidazolyl substituted with one or two independently
selected alkyl groups groups, and (e) G.sup.5 is selected from the
group consisting of --N.dbd., --NH--, --O-- and --S--, and (f)
G.sup.6 is C or CH.
[0630] In another embodiment of this invention: (a) R.sup.1 is a
methyl or ethyl group substituted with one phenyl, or (b) R.sup.1
is an methyl or alkyl group substituted with one phenyl, and said
phenyl is substituted with 1 to 3 F, and (c) R.sup.10 is phenyl
substituted with one --OR.sup.15 group, wherein R.sup.15 is methyl,
and (d) R.sup.9 is selected from the group consisting of imidazolyl
and imidazolyl substituted with one methyl group.
[0631] In another embodiment of this invention: (a) R.sup.1 is a
methyl or ethyl group substituted with one phenyl, or (b) R.sup.1
is an methyl or alkyl group substituted with one phenyl, and said
phenyl is substituted with 1 to 3 F, and (c) R.sup.10 is phenyl
substituted with one --OR.sup.15 group, wherein R.sup.15 is methyl,
and (d) R.sup.9 is selected from the group consisting of imidazolyl
and imidazolyl substituted with one methyl group, and (e) G.sup.5
is selected from the group consisting of --N.dbd., --NH--, --O--
and --S--.
[0632] In another embodiment of this invention: (a) R.sup.1 is a
methyl or ethyl group substituted with one phenyl, or (b) R.sup.1
is an methyl or alkyl group substituted with one phenyl, and said
phenyl is substituted with 1 to 3 F, and (c) R.sup.10 is phenyl
substituted with one --OR.sup.15 group, wherein R.sup.15 is methyl,
and (d) R.sup.9 is selected from the group consisting of imidazolyl
and imidazolyl substituted with one methyl group, and (e) G.sup.5
is selected from the group consisting of --N.dbd., --NH--, --O--
and --S--, and (f) G.sup.6 is C or CH.
[0633] In another embodiment of this invention R.sup.1 is selected
from the group consisting of:
##STR00120##
and wherein the R.sup.9-R.sup.10-moiety is:
##STR00121##
[0634] In another embodiment of this invention R.sup.1 is selected
from the group consisting of:
##STR00122##
and wherein the R.sup.9-R.sup.10-moiety is:
##STR00123##
and G.sup.5 is selected from the group consisting of --NH--, --O--
and --S--, and G.sup.6 is C or CH.
[0635] In another embodiment of this invention R.sup.1 is selected
from the group consisting of:
##STR00124##
and wherein the R.sup.9-R.sup.10-moiety is:
##STR00125##
[0636] In another embodiment of this invention R.sup.1 is selected
from the group consisting of:
##STR00126##
and wherein the R.sup.9-R.sup.10-moiety is:
##STR00127##
and G.sup.5 is selected from the group consisting of --N.dbd.,
--NH--, --O-- and --S--, and G.sup.6 is C or CH.
[0637] In another embodiment of this invention R.sup.1 is selected
from the group consisting of:
##STR00128##
and wherein the R.sup.9-R.sup.10-moiety is:
##STR00129##
[0638] In another embodiment of this invention R.sup.1 is selected
from the group consisting of:
##STR00130##
and wherein the R.sup.9-R.sup.10-moiety is:
##STR00131##
and G.sup.5 is selected from the group consisting of --N.dbd.,
--NH--, --O-- and --S--, and G.sup.6 is C or CH.
[0639] In another embodiment of this invention R.sup.1 is selected
from the group consisting of:
##STR00132##
and wherein the R.sup.9-R.sup.10-moiety is:
##STR00133##
[0640] In another embodiment of this invention R.sup.1 is selected
from the group consisting of:
##STR00134##
and wherein the R.sup.9-R.sup.10-moiety is:
##STR00135##
and G.sup.5 is selected from the group consisting of --NH.dbd.,
--O-- and --S--, and G.sup.6 is C or CH.
[0641] In another embodiment of this invention R.sup.1 is selected
from the group consisting of:
##STR00136##
and wherein the R.sup.9-R.sup.10-moiety is:
##STR00137##
[0642] In another embodiment of this invention R.sup.1 is selected
from the group consisting of:
##STR00138##
and wherein the R.sup.9-R.sup.10-moiety is:
##STR00139##
and G.sup.5 is selected from the group consisting of --N.dbd.,
--NH--, --O-- and --S--, and G.sup.6 is C or CH.
[0643] Other embodiments of this invention are directed to
compounds of formula (I) wherein R.sup.1 is selected from the group
consisting of: benzofusedcycloalkyl (i.e., fused benzocycloalkyl),
fused benzoheterocycloalkyl, fused heteroarylcycloalkyl, fused
heteroarylheterocycloalkyl, and wherein said R.sup.1 groups are
optionally substituted with 1-5 independently selected R.sup.21
groups. In one example, the R.sup.21 groups are halo (e.g., F).
[0644] Examples of the fused ring R.sup.1 groups include, but are
not limited to:
##STR00140##
wherein each Y is independently selected from the group consisting
of: --O--, --NR.sup.14-- and --C(R.sup.21).sub.q--, wherein q is as
defined above (i.e., 0, 1 or 2 and each R.sup.21 is independently
selected), and wherein R.sup.14 and R.sup.21 are as defined for
formula (I). Examples of these R.sup.1 groups include, for
example:
##STR00141##
[0645] Compounds of formula (I) also include compounds wherein
R.sup.1 is an alkyl group (e.g., ethyl) substituted with one
R.sup.21 group. Examples of said R.sup.1 groups include alkyl
(e.g., methyl or ethyl) substituted with the R.sup.21 moiety aryl
(e.g., phenyl or naphthyl). Examples of said R.sup.1 groups also
include alkyl (e.g., methyl or ethyl) substituted with the R.sup.21
moiety aryl (e.g., phenyl or naphthyl), which in turn is
substituted with one or more (e.g., one or two) independently
selected R.sup.22 groups (e.g., R.sup.22 is halo, such as, for
example, F).
[0646] Examples of the substituted R.sup.1 alkyl groups include,
but are not limited to:
##STR00142##
[0647] Other embodiments of this invention are directed to
compounds of formula (I) wherein R.sup.1 is a cycloalkyl group
(e.g., cyclopropyl or cyclobutyl) substituted with one R.sup.21
group (e.g., aryl, such as, for example, phenyl), or a cycloalkyl
group (e.g., cyclopentyl or cyclohexyl) substituted with one
R.sup.21 group (e.g., aryl, such as, for example, phenyl) which in
turn is substituted with one or more (e.g., one or two)
independently selected R.sup.22 groups (e.g., halo, such as, for
example, F). In one example the R.sup.21 group is bound to the same
carbon of the R.sup.1 group that binds the R.sup.1 group to the
rest of the molecule.
[0648] Examples of the cycloalkyl R.sup.1 groups include, but are
not limited to:
##STR00143##
such as, for example,
##STR00144##
wherein s is 0 (i.e., the ring is cyclopropyl), or 1 (i.e., the
ring is cyclobutyl). Examples of these R.sup.1 groups include, but
are not limited to:
##STR00145##
such as, for example,
##STR00146##
wherein s is 0 (i.e., the ring is cyclopropyl), or 1 (i.e., the
ring is cyclobutyl).
[0649] Other embodiments of this invention are directed to
compounds of formula (I) wherein R.sup.1 is
##STR00147##
##STR00148##
wherein Z is selected from the group consisting of: (1) --O--, (2)
--NR.sup.14--, (3) --C(R.sup.21).sub.q-- wherein q is 0, 1 or 2,
and each R.sup.21 is independently selected, (4)
--C(R.sup.21).sub.q--C(R.sup.21).sub.q-- wherein each q is
independently 0, 1 or 2 and each R.sup.21 is independently
selected, (5)
--(C(R.sup.21).sub.q).sub.q--O--(C(R.sup.21).sub.q).sub.q-- wherein
each q is independently 0, 1 or 2, and each R.sup.21 is
independently selected, and (6)
--(C(R.sup.21).sub.q).sub.q--N(R.sup.14)--(C(R.sup.21).sub.q).sub.q--
wherein each q is independently 0, 1 or 2, and each R.sup.21 is
independently selected. Examples of R.sup.21 include, but are not
limited to, aryl (e.g., phenyl) and aryl (e.g., phenyl) substituted
with one or more (e.g., one or two, or one) independently selected
R.sup.22 groups (e.g., halo, such as, for example, F). Examples of
this R.sup.1 include, but are not limited to:
##STR00149##
Thus, examples of this R.sup.1 group include, but are not limited
to:
##STR00150##
Examples of R.sup.1 also include, but are not limited to:
##STR00151##
Examples of the R.sup.1 group
##STR00152##
also include, but are not limited to:
##STR00153##
Examples of the R.sup.1 group
##STR00154##
also include, but are not limited to:
##STR00155##
Examples of the R.sup.1 group
##STR00156##
also include, but are not limited to:
##STR00157##
Examples of the R group
##STR00158##
also include, but are not limited to:
##STR00159##
[0650] Other embodiments of this invention are directed to
compounds of formula (I) wherein R.sup.10 is aryl (e.g., phenyl) or
aryl (e.g., phenyl) substituted with one or more (e.g., one or two,
or one) R.sup.21 groups (e.g., --OR.sup.15, wherein, for example,
R.sup.15 is alkyl, such as, for example, methyl), and R.sup.9 is
heteroaryl (e.g., imidazolyl) or heteroaryl (e.g., imidazolyl)
substituted with one or more (e.g., one or two, or one) R.sup.21
groups (e.g., alkyl, such as, for example, methyl).
[0651] Other embodiments of this invention are directed to the
compounds of formula (I) wherein R.sup.10 is heteroaryl or
heteroaryl substituted with one or more R.sup.21 groups, and
R.sup.9 is heteroaryl (e.g., imidazolyl) or heteroaryl (e.g.,
imidazolyl) substituted with one or more (e.g., one or two, or one)
R.sup.21 groups (e.g., alkyl, such as, for example, methyl).
[0652] In another embodiment of the compounds of formula (I)
R.sup.10 is aryl substituted with one R.sup.21 group, wherein said
R.sup.21 group is --OR.sup.15. In one example, R.sup.15 is alkyl.
In another example R.sup.15 is methyl.
[0653] In another embodiment of the compounds of formula (I)
R.sup.10 is phenyl substituted with one R.sup.21 group, wherein
said R.sup.21 group is --OR.sup.15. In one example, R.sup.15 is
alkyl. In another example R.sup.15 is methyl.
[0654] In another embodiment of the compounds of formula (I)
R.sup.10 is heteroaryl.
[0655] In another embodiment of the compounds of formula (I)
R.sup.9 is heteroaryl,
[0656] In another embodiment of the compounds of formula (I)
R.sup.9 is heteroaryl substituted with one or more (e.g., one)
independently selected R.sup.21 groups.
[0657] In another embodiment of the compounds of formula (I)
R.sup.9 is heteroaryl substituted with one or more (e.g., one)
independently selected R.sup.21 groups, wherein each R.sup.21 group
is the same or different alkyl group (e.g., methyl).
[0658] In another embodiment of the compounds of formula (I)
R.sup.9 is heteroaryl substituted with one R.sup.21 group.
[0659] In another embodiment of the compounds of formula (I)
R.sup.9 is heteroaryl substituted with one R.sup.21 group, wherein
R.sup.21 is an alkyl group (e.g., methyl).
[0660] In another embodiment of the compounds of formula (I)
R.sup.9 is imidazolyl.
[0661] In another embodiment of the compounds of formula (I)
R.sup.9 is imidazolyl substituted with one or more (e.g., one)
independently selected R.sup.21 groups.
[0662] In another embodiment of the compounds of formula (I)
R.sup.9 is imidazolyl substituted with one or more (e.g., one)
independently selected R.sup.21 groups, wherein each R.sup.21 group
is the same or different alkyl group (e.g., methyl).
[0663] In another embodiment of the compounds of formula (I)
R.sup.9 is imidazolyl substituted with one R.sup.21 group.
[0664] In another embodiment of the compounds of formula (I)
R.sup.9 is imidazolyl substituted with one R.sup.21 group, wherein
R.sup.21 is an alkyl group (e.g., methyl).
[0665] In another embodiment of the compounds of formula (I)
R.sup.9 is heteroaryl, optionally substituted with one or more
R.sup.21 groups, and R.sup.10 is aryl optionally substituted with
one or more (e.g., one) R.sup.21 groups.
[0666] In another embodiment of the compounds of formula (I)
R.sup.9 is heteroaryl, optionally substituted with one R.sup.21
group, and R.sup.10 is aryl optionally substituted with one
R.sup.21 group.
[0667] In another embodiment of the compounds of formula (I)
R.sup.9 is heteroaryl, optionally substituted with one or more
R.sup.21 groups, and R.sup.10 is phenyl optionally substituted with
one or more (e.g., one) R.sup.21 groups.
[0668] In another embodiment of the compounds of formula (I)
R.sup.9 is heteroaryl, optionally substituted with one R.sup.21
group, and R.sup.10 is phenyl optionally substituted with one
R.sup.21 group.
[0669] In another embodiment of the compounds of formula (I)
R.sup.9 is imidazolyl, optionally substituted with one or more
R.sup.21 groups, and R.sup.10 is aryl optionally substituted with
one or more (e.g., one) R.sup.21 groups.
[0670] In another embodiment of the compounds of formula (I)
R.sup.9 is imidazolyl, optionally substituted with one R.sup.21
group, and R.sup.10 is aryl optionally substituted with one
R.sup.21 group.
[0671] In another embodiment of the compounds of formula (I)
R.sup.9 is imidazolyl, optionally substituted with one or more
R.sup.21 groups, and R.sup.10 is phenyl optionally substituted with
one or more (e.g., one) R.sup.21 groups.
[0672] In another embodiment of the compounds of formula (I)
R.sup.9 is imidazolyl, optionally substituted with one R.sup.21
group, and R.sup.10 is phenyl optionally substituted with one
R.sup.21 group.
[0673] Other embodiments of the compounds of formula (I) are
directed to any one of the above embodiments wherein R.sup.9
is:
##STR00160##
[0674] Other embodiments of the compounds of formula (I) are
directed to any one of the above embodiments wherein R.sup.10
is:
##STR00161##
(wherein the --OR.sup.15 is ortho to the carbon to which R.sup.9 is
bound to, i.e., the R.sup.9-R.sup.10-- moiety is:
##STR00162##
[0675] Other embodiments for the compounds of formula (I) are
directed to any one of the above embodiments wherein R.sup.10
is:
##STR00163##
(wherein the --OCH.sub.3 is ortho to the carbon to which R.sup.9 is
bound to, i.e., the R.sup.9-R.sup.10-- moiety is:
##STR00164##
[0676] In another embodiment of the compounds of formula (R.sup.1
is benzofusedcycloalkyl.
[0677] In another embodiment of the compounds of formula (I)
R.sup.1 is:
##STR00165##
[0678] In another embodiment of the compounds of formula (I)
R.sup.1 is:
##STR00166##
[0679] In another embodiment of the compounds of formula (I)
R.sup.1 is:
##STR00167##
[0680] In another embodiment of the compounds of formula (I)
R.sup.1 is:
##STR00168##
[0681] In another embodiment of the compounds of formula (I)
R.sup.1 is alkyl substituted with one R.sup.21 group.
[0682] In another embodiment of the compounds of formula (I)
R.sup.1 is alkyl substituted with one R.sup.21 group, and said
alkyl is
##STR00169##
[0683] In another embodiment of the compounds of formula (I)
R.sup.1 is alkyl (e.g., (a), (b) or (c) described above)
substituted with one R.sup.21 group wherein said R.sup.21 group is
aryl.
[0684] In another embodiment of the compounds of formula (I)
R.sup.1 is alkyl (e.g., (a), (b) or (c) described above)
substituted with one R.sup.21 group wherein said R.sup.21 group is
phenyl.
[0685] In another embodiment of the compounds of formula (I)
R.sup.1 is alkyl (e.g., (a), (b) or (c) described above)
substituted with one R.sup.21 group wherein said R.sup.21 group is
naphthyl.
[0686] In another embodiment of the compounds of formula (I)
R.sup.1 is alkyl substituted with one R.sup.21 group, and said
R.sup.21 group is substituted with two independently selected
R.sup.22 groups.
[0687] In another embodiment of the compounds of formula (I)
R.sup.1 is alkyl substituted with one R.sup.21 group, and said
R.sup.21 group is substituted with one R.sup.22 group.
[0688] In another embodiment of the compounds of formula (I)
R.sup.1 is alkyl substituted with one R.sup.21 group, wherein said
alkyl group is (a) (e.g., (b) or (c)), as described above, and said
R.sup.21 group is substituted with two independently selected
R.sup.22 groups.
[0689] In another embodiment of the compounds of formula (I)
R.sup.1 is alkyl substituted with one R.sup.21 group, wherein said
alkyl group is (a) (e.g., (b) or (c)), as described above, and said
R.sup.21 group is substituted with one R.sup.22 group.
[0690] In another embodiment of the compounds of formula (I)
R.sup.1 is alkyl substituted with one R.sup.21 group, wherein said
R.sup.21 group is aryl, and said R.sup.21 group is substituted with
two independently selected R.sup.22 groups.
[0691] In another embodiment of the compounds of formula (I)
R.sup.1 is alkyl substituted with one R.sup.21 group, wherein said
R.sup.21 group is aryl, and said R.sup.21 group is substituted with
one R.sup.22 group.
[0692] In another embodiment of the compounds of formula (I)
R.sup.1 is alkyl substituted with one R.sup.21 group, wherein said
R.sup.21 group is aryl, said alkyl group is (a) (e.g., (b) or (c)),
as described above, and said R.sup.21 group is substituted with two
independently selected R.sup.22 groups.
[0693] In another embodiment of the compounds of formula (I)
R.sup.1 is alkyl substituted with one R.sup.21 group, wherein said
R.sup.21 group is aryl, wherein said alkyl group is (a) (e.g., (b)
or (c)), as described above, and said R.sup.21 group is substituted
with one R.sup.22 group.
[0694] In another embodiment of the compounds of formula (I)
R.sup.1 is alkyl substituted with one R.sup.21 group, wherein said
R.sup.21 group is aryl, said R.sup.21 group is substituted with two
independently selected R.sup.22 groups, and each R.sup.22 is
halo.
[0695] In another embodiment of the compounds of formula (I)
R.sup.1 is alkyl substituted with one R.sup.21 group, wherein said
R.sup.21 group is aryl, and said R.sup.21 group is substituted with
one R.sup.22 group, and said R.sup.22 is halo.
[0696] In another embodiment of the compounds of formula (I)
R.sup.1 is alkyl substituted with one R.sup.21 group, wherein said
R.sup.21 group is aryl, said alkyl group is (a) (e.g., (b) or (c)),
as described above, and said R.sup.21 group is substituted with two
independently selected R.sup.22 groups, and each R.sup.22 is
halo.
[0697] In another embodiment of the compounds of formula (I)
R.sup.1 is alkyl substituted with one R.sup.21 group, wherein said
R.sup.21 group is aryl, wherein said alkyl group is (a) (e.g., (b)
or (c)), as described above, and said R.sup.21 group is substituted
with one R.sup.22 group. and said R.sup.22 is halo.
[0698] In another embodiment of the compounds of formula (I)
R.sup.1 is alkyl substituted with: one R.sup.21 group, wherein said
R.sup.21 group is aryl, said R.sup.21 group is substituted with two
independently selected R.sup.22 groups, and each R.sup.22 is F.
[0699] In another embodiment of the compounds of formula (I)
R.sup.1 is alkyl substituted with one R.sup.21 group, wherein said
R.sup.21 group is aryl, and said R.sup.21 group is substituted with
one R.sup.22 group, and said R.sup.22 is F.
[0700] In another embodiment of the compounds of formula (I)
R.sup.1 is alkyl substituted with one R.sup.21 group, wherein said
R.sup.21 group is aryl, said alkyl group is (a) (e.g., (b) or (c)),
as described above, and said R.sup.21 group is substituted with two
independently selected R.sup.22 groups, and each R.sup.22 is F.
[0701] In another embodiment of the compounds of formula (I)
R.sup.1 is alkyl substituted with one R.sup.21 group, wherein said.
R.sup.21 group is aryl, wherein said alkyl group is (a) (e.g., (b)
or (c)), as described above, and said R.sup.21 group is substituted
with one R.sup.22 group. and said R.sup.22 is F.
[0702] In another embodiment of the compounds of formula (I)
R.sup.1 is:
##STR00170##
[0703] In another embodiment of the compounds of formula (I)
R.sup.1 is:
##STR00171##
[0704] In another embodiment of the compounds of formula (I)
R.sup.1 is:
##STR00172##
[0705] In another embodiment of the compounds of formula (I)
R.sup.1 is:
##STR00173##
[0706] In another embodiment of the compounds of formula (I)
R.sup.1 is:
##STR00174##
[0707] In another embodiment of this invention R.sup.1 is:
##STR00175##
[0708] Other embodiments of this invention are directed to any one
of the embodiments directed to R.sup.1 wherein the compound of
formula (I) is a compound of formula (IA).
[0709] Other embodiments of this invention are directed to any one
of the embodiments directed to R.sup.1 wherein the compound of
formula (I) is a compound of formula (IB).
[0710] Other embodiments of this invention are directed to any one
of the embodiments directed to R.sup.9 wherein the compound of
formula (I) is a compound of formula (IA).
[0711] Other embodiments of this invention are directed to any one
of the embodiments directed to R.sup.9 wherein the compound of
formula (I) is a compound of formula (IB).
[0712] Other embodiments of this invention are directed to any one
of the embodiments directed to R.sup.10 wherein the compound of
formula (I) is a compound of formula (IA).
[0713] Other embodiments of this invention are directed to any one
of the embodiments directed to R.sup.10 wherein the compound of
formula (I) is a compound of formula (IB).
[0714] Other embodiments of this invention are directed to any one
of the embodiments directed to R.sup.9 and R.sup.10 wherein the
compound of formula (I) is a compound of formula (IA).
[0715] Other embodiments of this invention are directed to any one
of the embodiments directed to R.sup.9 and R.sup.10 wherein the
compound of formula (I) is a compound of formula (IB).
[0716] Examples of R.sup.21 groups include --OR.sup.15 wherein, for
example, R.sup.15 is alkyl (such as methyl or ethyl), or R.sup.15
is cycloalkylalkyl (such as, for example, --CH.sub.2-cyclopropyl),
or R.sup.15 is -alkyl-(R.sup.18).sub.n (wherein, for example, said
R.sup.18 is --OR.sup.20, and said R.sup.20 is alkyl, and wherein
examples of said -alkyl-(R.sup.18).sub.n moiety is
--(CH.sub.2).sub.2OCH.sub.3).
[0717] Examples of R.sup.21 also include --C(O)OR.sup.15 wherein,
for example, R.sup.15 is alkyl, such as, for example, methyl).
[0718] Examples of R.sup.21 also include --C(O)NR.sup.15R.sup.16,
wherein, for example, one of R.sup.15 or R.sup.16 is H, and the
other is selected from the group consisting of:
(R.sup.18).sub.n-arylalkyl-, (R.sup.18).sub.n-alkyl-, and
cycloalkyl. In one example of this --C(O)NR.sup.15R.sup.16 moiety
the R.sup.18 is --OR.sup.20, n is 1, R.sup.20 is alkyl, said
cycloalkyl is cyclobutyl, and said arylalkyl- is benzyl.
[0719] Examples of R.sup.21 also include halo (e.g., Br, Cl or
F).
[0720] Examples of R.sup.21 also include arylalkyl, such as, for
example, benzyl. Other embodiments of this invention are directed
to any one of the embodiments for formula (I) wherein the formula
is formula (IA).
[0721] Other embodiments of this invention are directed to any one
of the embodiments for formula (I) wherein the formula is formula
(IB).
[0722] In another embodiment of this invention the optional bond
between G.sup.1 and G.sup.2 in formula (IA) is absent (i.e., there
is a single bond between G.sup.1 and G.sup.2).
[0723] In another embodiment of this invention the optional bond
between G.sup.1 and G.sup.2 in formula (IA) is present (i.e., there
is a double bond between G.sup.1 and G.sup.2).
[0724] In another embodiment of this invention the optional bond
between G.sup.1 and G.sup.2 in formula (IB) is absent (i.e., there
is a single bond between G.sup.1 and G.sup.2).
[0725] In another embodiment of this invention the optional bond
between G.sup.1 and G.sup.2 in formula (IB) is present (i.e., there
is a double bond between G.sup.1 and G2).
[0726] Another embodiment of this invention is directed to
compounds of formula (I) having the formula:
##STR00176##
[0727] In one embodiment of this invention R.sup.1 in compound 43A
is aryl or substituted aryl. In another embodiment R.sup.1 in
compound 43A is phenyl or substituted phenyl. In another embodiment
R.sup.1 in compound 43A is phenyl substituted with 1 to 3
independently selected R.sup.21 groups. In another embodiment of
this invention R.sup.1 in compound 43A is phenyl substituted with 1
to 3 (e.g., 1 to 3, or 1 to 2, or 1) independently selected halos.
In another embodiment of this invention R.sup.1 in compound 43A is
phenyl substituted with 1 to 3 (e.g., 1 to 3, or 1 to 2, or 1) F
atoms.
In another embodiment of this invention R.sup.1 in compound 43A is
phenyl substituted with 1 F atom.
[0728] Another embodiment of this invention is directed to
compounds of formula (I) having the formula:
##STR00177##
[0729] In one embodiment of this invention R.sup.1 in compound 43
is aryl or substituted aryl. In another embodiment R.sup.1 in
compound 43 is phenyl or substituted phenyl. In another embodiment
R.sup.1 in compound 43 is phenyl substituted with 1 to 3
independently selected R.sup.21 groups. In another embodiment of
this invention R.sup.1 in compound 43 is phenyl substituted with 1
to 3 (e.g., 1 to 3, or 1 to 2, or 1) independently selected halos.
In another embodiment of this invention R.sup.1 in compound 43 is
phenyl substituted with 1 to 3 (e.g., 1 to 3, or 1 to 2, or 1) F
atoms. In another embodiment of this invention R.sup.1 in compound
43 is phenyl substituted with 1 F atom.
[0730] Another embodiment of this invention is directed to
compounds of formula (I) having the formula:
##STR00178##
In one embodiment of this invention R in compound 44A is aryl or
substituted aryl. In another embodiment R.sup.1 in compound 44A is
phenyl or substituted phenyl. In another embodiment R.sup.1 in
compound 44A is phenyl substituted with 1 to 3 independently
selected R.sup.21 groups. In another embodiment of this invention
R.sup.1 in compound 44A is phenyl substituted with 1 to 3 (e.g., 1
to 3, or 1 to 2, or 1) independently selected halos. In another
embodiment of this invention R.sup.1 in compound 44A is phenyl
substituted with 1 to 3 (e.g., 1 to 3, or 1 to 2, or 1) F atoms. In
another embodiment of this invention R.sup.1 in compound 44A is
phenyl substituted with 1 F atom.
[0731] Another embodiment of this invention is directed to
compounds of formula formula (I) having the formula:
##STR00179##
In one embodiment of this invention R.sup.1 in compound 44 is aryl
or substituted aryl. In another embodiment R.sup.1 in compound 44
is phenyl or substituted phenyl. In another embodiment R.sup.1 in
compound 44 is phenyl substituted with 1 to 3 independently
selected R.sup.21 groups. In another embodiment of this invention
R.sup.1 in compound 44 is phenyl substituted with 1 to 3 (e.g., 1
to 3, or 1 to 2, or 1) independently selected halos. In another
embodiment of this invention R.sup.1 in compound 44 is phenyl
substituted with 1 to 3 (e.g., 1 to 3, or 1 to 2, or 1) F atoms. In
another embodiment of this invention R.sup.1 in compound 44 is
phenyl substituted with 1 F atom.
[0732] Another embodiment of this invention is directed to
compounds of formula formula (I) having the formula:
##STR00180##
In one embodiment of this invention R in compound 45A is aryl or
substituted aryl. In another embodiment R.sup.1 in compound 45A is
phenyl or substituted phenyl. In another embodiment R.sup.1 in
compound 45A is phenyl substituted with 1 to 3 independently
selected R.sup.21 groups. In another embodiment of this invention
R.sup.1 in compound 45A is phenyl substituted with 1 to 3 (e.g., 1
to 3, or 1 to 2, or 1) independently selected halos. In another
embodiment of this invention R.sup.1 in compound 45A is phenyl
substituted with 1 to 3 (e.g., 1 to 3, or 1 to 2, or 1) F atoms. In
another embodiment of this invention R.sup.1 in compound 45A is
phenyl substituted with 1 F atom.
[0733] Another embodiment of this invention is directed to
compounds of formula formula (I) having the formula:
##STR00181##
In one embodiment of this invention R.sup.1 in compound 45 is aryl
or substituted aryl. In another embodiment R.sup.1 in compound 45
is phenyl or substituted phenyl. In another embodiment R.sup.1 in
compound 45 is phenyl substituted with 1 to 3 independently
selected R.sup.21 groups. In another embodiment of this invention
R.sup.1 in compound 45 is phenyl substituted with 1 to 3 (e.g., 1
to 3, or 1 to 2, or 1) independently selected halos. In another
embodiment of this invention R.sup.1 in compound 45 is phenyl
substituted with 1 to 3 (e.g., 1 to 3, or 1 to 2, or 1) F atoms. In
another embodiment of this invention R.sup.1 in compound 45 is
phenyl substituted with 1 F atom.
[0734] Another embodiment of this invention is directed to
compounds of formula formula (I) having the formula:
##STR00182##
In one embodiment of this invention R.sup.1 in compound 46A is aryl
or substituted aryl. In another embodiment R.sup.1 in compound 46A
is phenyl or substituted phenyl. In another embodiment R.sup.1 in
compound 46A is phenyl substituted with 1 to 3 independently
selected R.sup.21 groups. In another embodiment of this invention
R.sup.1 in compound 46A is phenyl substituted with 1 to 3 (e.g., 1
to 3, or 1 to 2, or 1) independently selected halos. In another
embodiment of this invention R.sup.1 in compound 46A is phenyl
substituted with 1 to 3 (e.g., 1 to 3, or 1 to 2, or 1) F atoms. In
another embodiment of this invention R.sup.1 in compound 46A is
phenyl substituted with 1 F atom.
[0735] Another embodiment of this invention is directed to
compounds of formula formula (I) having the formula:
##STR00183##
In one embodiment of this invention R.sup.1 in compound 46 is aryl
or substituted aryl. In another embodiment R.sup.1 in compound 46
is phenyl or substituted phenyl. In another embodiment R.sup.1 in
compound 46 is phenyl substituted with 1 to 3 independently
selected R.sup.21 groups. In another embodiment of this invention
R.sup.1 in compound 46 is phenyl substituted with 1 to 3 (e.g., 1
to 3, or 1 to 2, or 1) independently selected halos. In another
embodiment of this invention R.sup.1 in compound 46 is phenyl
substituted with 1 to 3 (e.g., 1 to 3, or 1 to 2, or 1) F atoms. In
another embodiment of this invention R.sup.1 in compound 46 is
phenyl substituted with 1 F atom.
[0736] Another embodiment of this invention is directed to
compounds of formula formula (I) having the formula:
##STR00184##
In one embodiment of this invention R.sup.1 in compound 47A is aryl
or substituted aryl. In another embodiment R.sup.1 in compound 47A
is phenyl or substituted phenyl. In another embodiment R.sup.1 in
compound 47A is phenyl substituted with 1 to 3 independently
selected R.sup.21 groups. In another embodiment of this invention R
compound 47A is phenyl substituted with 1 to 3 (e.g., 1 to 3, or 1
to 2, or 1) independently selected halos. In another embodiment of
this invention R.sup.1 in compound 47A is phenyl substituted with 1
to 3 (e.g., 1 to 3, or 1 to 2, or 1) F atoms. In another embodiment
of this invention R.sup.1 in compound 47A is phenyl substituted
with 1 F atom.
[0737] Another embodiment of this invention is directed to
compounds of formula formula (I) having the formula:
##STR00185##
In one embodiment of this invention R.sup.1 in compound 47 is aryl
or substituted aryl. In another embodiment R.sup.1 in compound 47
is phenyl or substituted phenyl. In another embodiment R.sup.1 in
compound 47 is phenyl substituted with 1 to 3 independently
selected R.sup.21 groups. In another embodiment of this invention
R.sup.1 in compound 47 is phenyl substituted with 1 to 3 (e.g., 1
to 3, or 1 to 2, or 1) independently selected halos. In another
embodiment of this invention R.sup.1 in compound 47 is phenyl
substituted with 1 to 3 (e.g., 1 to 3, or 1 to 2, or 1) F atoms. In
another embodiment of this invention R.sup.1 in compound 47 is
phenyl substituted with 1 F atom.
[0738] Another embodiment of this invention is directed to
compounds of formula formula (I) having the formula:
##STR00186##
In one embodiment of this invention R in compound 48A is aryl or
substituted aryl. In another embodiment R.sup.1 in compound 48A is
phenyl or substituted phenyl. In another embodiment R.sup.1 in
compound 48A is phenyl substituted with 1 to 3 independently
selected R.sup.21 groups. In another embodiment of this invention
R.sup.1 in compound 48A is phenyl substituted with 1 to 3 (e.g., 1
to 3, or 1 to 2, or 1) independently selected halos. In another
embodiment of this invention R.sup.1 in compound 48A is phenyl
substituted with 1 to 3 (e.g., 1 to 3, or 1 to 2, or 1) F atoms. In
another embodiment of this invention R.sup.1 in compound 48A is
phenyl substituted with 1 F atom.
[0739] Another embodiment of this invention is directed to
compounds of formula formula (I) having the formula:
##STR00187##
In one embodiment of this invention R.sup.1 in compound 48 is aryl
or substituted aryl. In another embodiment R.sup.1 in compound 48
is phenyl or substituted phenyl. In another embodiment R.sup.1 in
compound 48 is phenyl substituted with 1 to 3 independently
selected R.sup.21 groups. In another embodiment of this invention
R.sup.1 in compound 48 is phenyl substituted with 1 to 3 (e.g., 1
to 3, or 1 to 2, or 1) independently selected halos. In another
embodiment of this invention R.sup.1 in compound 48 is phenyl
substituted with 1 to 3 (e.g., 1 to 3, or 1 to 2, or 1) F atoms. In
another embodiment of this invention R.sup.1 in compound 48 is
phenyl substituted with 1 F atom.
[0740] Another embodiment of this invention is directed to
compounds of formula (formula (I) having the formula:
##STR00188##
In one embodiment of this invention R.sup.1 in compound 49A is aryl
or substituted aryl. In another embodiment R.sup.1 in compound 49A
is phenyl or substituted phenyl. In another embodiment R.sup.1 in
compound 49A is phenyl substituted with 1 to 3 independently
selected R.sup.21 groups. In another embodiment of this invention
R.sup.1 in compound 49A is phenyl substituted with 1 to 3 (e.g., 1
to 3, or 1 to 2, or 1) independently selected halos. In another
embodiment of this invention R.sup.1 in compound 49A is phenyl
substituted with 1 to 3 (e.g., 1 to 3, or 1 to 2, or 1) F atoms. In
another embodiment of this invention R.sup.1 in compound 49A is
phenyl substituted with 1 F atom.
[0741] Another embodiment of this invention is directed to
compounds of formula formula (I) having the formula:
##STR00189##
In one embodiment of this invention R.sup.1 in compound 49 is aryl
or substituted aryl. In another embodiment R.sup.1 in compound 49
is phenyl or substituted phenyl. In another embodiment R.sup.1 in
compound 49 is phenyl substituted with 1 to 3 independently
selected R.sup.21 groups. In another embodiment of this invention
R.sup.1 in compound 49 is phenyl substituted with 1 to 3 (e.g., 1
to 3, or 1 to 2, or 1) independently selected halos. In another
embodiment of this invention R.sup.1 in compound 49 is phenyl
substituted with 1 to 3 (e.g., 1 to 3, or 1 to 2, or 1) F atoms. In
another embodiment of this invention R.sup.1 in compound 49 is
phenyl substituted with 1 F atom.
[0742] Another embodiment of this invention is directed to
compounds of formula formula (I) having the formula:
##STR00190##
wherein each R.sup.2 is independently selected. In one embodiment
of this invention R.sup.1 in compound 50A is aryl or substituted
aryl. In another embodiment R.sup.1 in compound 50A is phenyl or
substituted phenyl. In another embodiment R.sup.1 in compound 50A
is phenyl substituted with 1 to 3 independently selected R.sup.21
groups. In another embodiment of this invention R.sup.1 in compound
50A is phenyl substituted with 1 to 3 (e.g., 1 to 3, or 1 to 2, or
1) independently selected halos. In another embodiment of this
invention R.sup.1 in compound 50A is phenyl substituted with 1 to 3
(e.g., 1 to 3, or 1 to 2, or 1) F atoms. In another embodiment of
this invention R.sup.1 in compound 50A is phenyl substituted with 1
F atom.
[0743] Another embodiment of this invention is directed to
compounds of formula formula (I) having the formula:
##STR00191##
wherein each R.sup.2 is independently selected. In one embodiment
of this invention R.sup.1 in compound 50 is aryl or substituted
aryl. In another embodiment R.sup.1 in compound 50 is phenyl or
substituted phenyl. In another embodiment R.sup.1 in compound 50 is
phenyl substituted with 1 to 3 independently selected R.sup.21
groups. In another embodiment of this invention R.sup.1 in compound
50 is phenyl substituted with 1 to 3 (e.g., 1 to 3, or 1 to 2, or
1) independently selected halos. In another embodiment of this
invention R.sup.1 in compound 50 is phenyl substituted with 1 to 3
(e.g., 1 to 3, or 1 to 2, or 1) F atoms. In another embodiment of
this invention R.sup.1 in compound 50 is phenyl substituted with 1
F atom.
[0744] Another embodiment of this invention is directed to
compounds of formula formula (I) having the formula:
##STR00192##
In one embodiment of this invention R.sup.1 in compound 51A is aryl
or substituted aryl. In another embodiment R.sup.1 in compound 51A
is phenyl or substituted phenyl. In another embodiment R.sup.1 in
compound 51A is phenyl substituted with 1 to 3 independently
selected R.sup.21 groups. In another embodiment of this invention
R.sup.1 in compound 51A is phenyl substituted with 1 to 3 (e.g., 1
to 3, or 1 to 2, or 1) independently selected halos. In another
embodiment of this invention R.sup.1 in compound 51A is phenyl
substituted with 1 to 3 (e.g., 1 to 3, or 1 to 2, or 1) F atoms. In
another embodiment of this invention R.sup.1 in compound 51A is
phenyl substituted with 1 F atom.
[0745] Another embodiment of this invention is directed to
compounds of formula formula (I) having the formula:
##STR00193##
In one embodiment of this invention R.sup.1 in compound 51 is aryl
or substituted aryl. In another embodiment R.sup.1 in compound 51
is phenyl or substituted phenyl. In another embodiment R.sup.1 in
compound 51 is phenyl substituted with 1 to 3 independently
selected R.sup.21 groups. In another embodiment of this invention
R.sup.1 in compound 51 is phenyl substituted with 1 to 3 (e.g., 1
to 3, or 1 to 2, or 1) independently selected halos. In another
embodiment of this invention R.sup.1 in compound 51 is phenyl
substituted with 1 to 3 (e.g., 1 to 3, or 1 to 2, or 1) F atoms. In
another embodiment of this invention R.sup.1 in compound 51 is
phenyl substituted with 1 F atom.
[0746] Another embodiment of this invention is directed to
compounds of formula formula (I) having the formula:
##STR00194##
In one embodiment of this invention R.sup.1 in compound 52A is aryl
or substituted aryl. In another embodiment R.sup.1 in compound 52A
is phenyl or substituted phenyl. In another embodiment R.sup.1 in
compound 52A is phenyl substituted with 1 to 3 independently
selected R.sup.21 groups. In another embodiment of this invention
R.sup.1 in compound 52A is phenyl substituted with 1 to 3 (e.g., 1
to 3, or 1 to 2, or 1) independently selected halos. In another
embodiment of this invention R.sup.1 in compound 52A is phenyl
substituted with 1 to 3 (e.g., 1 to 3, or 1 to 2, or 1) F atoms. In
another embodiment of this invention R.sup.1 in compound 52A is
phenyl substituted with 1 F atom.
[0747] Another embodiment of this invention is directed to
compounds of formula formula (I) having the formula:
##STR00195##
In one embodiment of this invention R.sup.1 in compound 52 is aryl
or substituted aryl. In another embodiment R.sup.1 in compound 52
is phenyl or substituted phenyl. In another embodiment R in
compound 52 is phenyl substituted with 1 to 3 independently
selected R.sup.21 groups. In another embodiment of this invention
R.sup.1 in compound 52 is phenyl substituted with 1 to 3 (e.g., 1
to 3, or 1 to 2, or 1) independently selected halos. In another
embodiment of this invention R.sup.1 in compound 52 is phenyl
substituted with 1 to 3 (e.g., 1 to 3, or 1 to 2, or 1) F atoms. In
another embodiment of this invention R.sup.1 in compound 52 is
phenyl substituted with 1 F atom.
[0748] Another embodiment of this invention is directed to
compounds of formula formula (I) having the formula:
##STR00196##
In one embodiment of this invention R.sup.1 in compound 53A is aryl
or substituted aryl. In another embodiment R.sup.1 in compound 53A
is phenyl or substituted phenyl. In another embodiment Win compound
53A is phenyl substituted with 1 to 3 independently selected
R.sup.21 groups. In another embodiment of this invention R.sup.1 in
compound 53A is phenyl substituted with Ito 3 (e.g., 1 to 3, or 1
to 2, or 1) independently selected halos. In another embodiment of
this invention R.sup.1 in compound 53A is phenyl substituted with 1
to 3 (e.g., 1 to 3, or 1 to 2, or 1) F atoms. In another embodiment
of this invention R.sup.1 in compound 53A is phenyl substituted
with 1 F atom.
[0749] Another embodiment of this invention is directed to
compounds of formula formula (I) having the formula:
##STR00197##
In one embodiment of this invention R.sup.1 in compound 53 is aryl
or substituted aryl. In another embodiment R.sup.1 in compound 53
is phenyl or substituted phenyl. In another embodiment R.sup.1 in
compound 53 is phenyl substituted with 1 to 3 independently
selected R.sup.21 groups. In another embodiment of this invention
R.sup.1 in compound 53 is phenyl substituted with 1 to 3 (e.g., 1
to 3, or 1 to 2, or 1) independently selected halos. In another
embodiment of this invention R.sup.1 in compound 53 is phenyl
substituted with 1 to 3 (e.g., 1 to 3, or 1 to 2, or 1) F atoms. In
another embodiment of this invention R.sup.1 in compound 53 is
phenyl substituted with 1 F atom.
[0750] Another embodiment of this invention is directed to
compounds of formula formula (I) having the formula:
##STR00198##
In one embodiment of this invention R.sup.1 in compound 54A is aryl
or substituted aryl. In another embodiment R.sup.1 in compound 54A
is phenyl or substituted phenyl. In another embodiment R.sup.1 in
compound 54A is phenyl substituted with 1 to 3 independently
selected R.sup.21 groups. In another embodiment of this invention
R.sup.1 in compound 54A is phenyl substituted with 1 to 3 (e.g., 1
to 3, or 1 to 2, or 1) independently selected halos. In another
embodiment of this invention R.sup.1 in compound 54A is phenyl
substituted with 1 to 3 (e.g., 1 to 3, or 1 to 2, or 1) F atoms. In
another embodiment of this invention R.sup.1 in compound 54A is
phenyl substituted with 1 F atom.
[0751] Another embodiment of this invention is directed to
compounds of formula formula (I) having the formula:
##STR00199##
In one embodiment of this invention R.sup.1 in compound 54 is aryl
or substituted aryl. In another embodiment R.sup.1 in compound 54
is phenyl or substituted phenyl. In another embodiment R.sup.1 in
compound 54 is phenyl substituted with 1 to 3 independently
selected R.sup.21 groups. In another embodiment of this invention
R.sup.1 in compound 54 is phenyl substituted with 1 to 3 (e.g., 1
to 3, or 1 to 2, or 1) independently selected halos. In another
embodiment of this invention R.sup.1 in compound 54 is phenyl
substituted with 1 to 3 (e.g., 1 to 3, or 1 to 2, or 1) F atoms. In
another embodiment of this invention R.sup.1 in compound 54 is
phenyl substituted with 1 F atom.
[0752] Examples of the R.sup.21 moiety in the embodiments of this
invention include, but are not limited to: (a) --OR.sup.15, (b)
--OR.sup.15 wherein R.sup.15 is alkyl, (c) --OR.sup.15 wherein
R.sup.15 is alkyl and said alkyl is methyl or ethyl. (d)
--OR.sup.15 wherein R.sup.15 is cycloalkylalkyl, (e) --OR.sup.15
wherein R.sup.15 is -alkyl-(R.sup.18).sub.n, (f) --OR.sup.15
wherein R.sup.15 is -alkyl-(R.sup.18).sub.n and wherein said
R.sup.18 is --OR.sup.20, (g) --OR.sup.15 wherein R.sup.15 is
-alkyl-(R.sup.18).sub.n and wherein said R.sup.18 is --OR.sup.20
and said R.sup.20 is alkyl. Examples of the R.sup.21 moiety include
but are not limited to: --OCH.sub.3, --OCH.sub.2CH.sub.3,
--O(CH.sub.2).sub.2OCH.sub.3, and --CH.sub.2-cyclopropyl.
[0753] Examples of R.sup.21 also include --C(O)OR.sup.15 wherein,
for example, R.sup.15 is alkyl, such as, for example, methyl).
[0754] Examples of R.sup.21 also include --C(O)NR.sup.15R.sup.16,
wherein, for example, one of R.sup.15 or R.sup.16 is H, and the
other is selected from the group consisting of:
(R.sup.18).sub.n-arylalkyl-, (R.sup.18).sub.n-alkyl-, and
cycloalkyl. In one example of this --C(O)NR.sup.15R.sup.16 moiety
the R.sup.18 is --OR.sup.20, n is 1, R.sup.20 is alkyl, said
cycloalkyl is cyclobutyl, and said arylalkyl- is benzyl.
[0755] Examples of R.sup.21 also include halo (e.g., Br, Cl or
F).
[0756] Examples of R.sup.21 also include arylalkyl, such as, for
example, benzyl.
[0757] formula (I) In another embodiment of this invention the
compound of formula (I) is a compound selected from the group
consisting of: 43A to 54A, and 43 to 54 wherein (a) R.sup.1 is a
methyl or ethyl group substituted with one phenyl, or (b) R.sup.1
is an methyl or ethyl group substituted with one phenyl, and said
phenyl is substituted with one, two, or three F.
[0758] In another embodiment of this invention the compound of
formula (I) is a compound selected from the group consisting of:
43A to 54A, and 43 to 54 wherein (a) R.sup.1 is a methyl or ethyl
group substituted with one phenyl, or (b) R.sup.1 is an methyl or
ethyl group substituted with one phenyl, and said phenyl is
substituted with one, two, or three F, and (c) R.sup.10 is phenyl
substituted with one --OR.sup.15 group, wherein R.sup.15 is methyl,
and (e) R.sup.9 is selected from the group consisting of imidazolyl
and imidazolyl substituted with one methyl group.
[0759] In another embodiment of this invention the compound of
formula (I) is a compound selected from the group consisting of:
43A to 54A, and 43 to 54 wherein R.sup.1 is selected from the group
consisting of:
##STR00200##
[0760] In another embodiment of this invention the compound of
formula (I) is a compound selected from the group consisting of:
43A to 54A, and 43 to 54 wherein R.sup.1 is selected from the group
consisting of:
##STR00201##
and wherein the R.sup.9-R.sup.10-moiety is:
##STR00202##
[0761] In another embodiment of this invention the compound of
formula (I) is a compound selected from the group consisting of:
43A to 54A, and 43 to 54 wherein R.sup.1 is selected from the group
consisting of:
##STR00203##
and wherein the R.sup.9-R.sup.10-moiety is:
##STR00204##
[0762] In another embodiment of this invention the compound of
formula (I) is a compound selected from the group consisting of:
43A to 54A, and 43 to 54 wherein R.sup.1 is selected from the group
consisting of:
##STR00205##
and wherein the R.sup.9R.sup.10-moiety is:
##STR00206##
[0763] In another embodiment of this invention the compound of
formula (I) is a compound selected from the group consisting of:
43A to 54A, and 43 to 54 wherein R.sup.1 is selected from the group
consisting of:
##STR00207##
and wherein the R.sup.9-R.sup.10-moiety is:
##STR00208##
[0764] In another embodiment of this invention the compound of
formula (I) is a compound selected from the group consisting of:
43A to 54A, and 43 to 54 wherein R.sup.1 is selected from the group
consisting of:
##STR00209##
and wherein the R.sup.9-R.sup.10-moiety is:
##STR00210##
[0765] Another embodiment of this invention is directed to a
compound of formula (I) selected from the group consisting of: IA,
IB, IA.1, IB.1, 43A to 54A, 43 to 54, 85.1, 88.1, 91.1, and 100 to
124.
[0766] Another embodiment of this invention is directed to a
compound of formula (I) selected from the group consisting of: 43A
to 54A, 43 to 54, 85.1, 88.1, 91.1, and 100 to 124.
[0767] Another embodiment of this invention is directed to a
compound of formula (I) selected from the group consisting of: IA,
IB, IA.1, and IB.1.
[0768] Another embodiment of this invention is directed to a
compound of formula (I) selected from the group consisting of: 43A
to 54A.
[0769] Another embodiment of this invention is directed to a
compound of formula (I) selected from the group consisting of: 43
to 54.
[0770] Another embodiment of this invention is directed to a
compound of formula (I) selected from the group consisting of:
85.1, 88.1, 91.1, and 100 to 124.
[0771] Another embodiment of this invention is directed to a
compound of formula (I) wherein said compound is 85.1.
[0772] Another embodiment of this invention is directed to a
compound of formula (I) wherein said compound is 88.1.
[0773] Another embodiment of this invention is directed to a
compound of formula (I) wherein said compound is 91.1.
[0774] Another embodiment of this invention is directed to a
compound of formula (I) wherein said compound is 100.
[0775] Another embodiment of this invention is directed to a
compound of formula (I) wherein said compound is 101.
[0776] Another embodiment of this invention is directed to a
compound of formula (I) wherein said compound is 102.
[0777] Another embodiment of this invention is directed to a
compound of formula (I) wherein said compound is 103.
[0778] Another embodiment of this invention is directed to a
compound of formula (I) wherein said compound is 104.
[0779] Another embodiment of this invention is directed to a
compound of formula (I) wherein said compound is 105.
[0780] Another embodiment of this invention is directed to a
compound of formula (I) wherein said compound is 106.
[0781] Another embodiment of this invention is directed to a
compound of formula (I) wherein said compound is 107.
[0782] Another embodiment of this invention is directed to a
compound of formula (I) wherein said compound is 108.
[0783] Another embodiment of this invention is directed to a
compound of formula (I) wherein said compound is 109.
[0784] Another embodiment of this invention is directed to a
compound of formula (I) wherein said compound is 110.
[0785] Another embodiment of this invention is directed to a
compound of formula (I) wherein said compound is 111.
[0786] Another embodiment of this invention is directed to a
compound of formula (I) wherein said compound is 112.
[0787] Another embodiment of this invention is directed to a
compound of formula (I) wherein said compound is 113.
[0788] Another embodiment of this invention is directed to a
compound of formula (I) wherein said compound is 114.
[0789] Another embodiment of this invention is directed to a
compound of formula (I) wherein said compound is 115.
[0790] Another embodiment of this invention is directed to a
compound of formula (I) wherein said compound is 116.
[0791] Another embodiment of this invention is directed to a
compound of formula (I) wherein said compound is 117.
[0792] Another embodiment of this invention is directed to a
compound of formula (I) wherein said compound is 118.
[0793] Another embodiment of this invention is directed to a
compound of formula (I) wherein said compound is 119.
[0794] Another embodiment of this invention is directed to a
compound of formula (I) wherein said compound is 120.
[0795] Another embodiment of this invention is directed to a
compound of formula (I) wherein said compound is 121.
[0796] Another embodiment of this invention is directed to a
compound of formula (I) wherein said compound is 122.
[0797] Another embodiment of this invention is directed to a
compound of formula (I) wherein said compound is 123.
[0798] Another embodiment of this invention is directed to a
compound of formula (I) wherein said compound is 124.
[0799] Another embodiment of this invention is directed to a
compound of formula (I) wherein said compound is IA.
[0800] Another embodiment of this invention is directed to a
compound of formula (I) wherein said compound is IA.1.
[0801] Another embodiment of this invention is directed to a
compound of formula (I) wherein said compound is IB.
[0802] Another embodiment of this invention is directed to a
compound of formula (I) wherein said compound is IB.1.
[0803] In the embodiments below Groups A, B, C, D, E, F, G and H
are as defined as follows: [0804] (1) Group A: compounds IA, IB,
IA.1, IB.1, 43A to 54A, 43 to 54, 85.1, 88.1, 91.1, and 100 to 124;
[0805] (2) Group B: compounds 43A to 54A, 43 to 54, 85.1, 88.1,
91.1, and 100 to 124; [0806] (3) Group C: compounds IA, IB, IA.1,
and IB.1; [0807] (4) Group D: compounds 43A to 54A; [0808] (5)
Group E: compounds 43 to 54; and [0809] (6) Group F: compounds
85.1, 88.1, 91.1, and 100 to 124.
[0810] Another embodiment of this invention is directed to a
compound of formula (I).
[0811] Another embodiment of this invention is directed to a
pharmaceutically acceptable salt of a compound of formula (I). And
in one example the salt is a salt of a compound selected from the
group consisting of Group A. And in another example the salt is a
salt of a compound selected from the group consisting of Group B.
And in another example the salt is a salt of a compound selected
from the group consisting of Group C. And in another example the
salt is a salt of a compound selected from the group consisting of
Group D. And in another example the salt is a salt of a compound
selected from the group consisting of Group E. And in another
example the salt is a salt of a compound selected from the group
consisting of Group F.
[0812] Another embodiment of this invention is directed to a
pharmaceutically acceptable ester of a compound of formula (I). And
in one example the ester is an ester of a compound selected from
the group consisting of Group A. And in another example the ester
is an ester of a compound selected from the group consisting of
Group B. And in another example the ester is an ester of a compound
selected from the group consisting of Group C. And in another
example the ester is an ester of a compound selected from the group
consisting of Group D. And in another example the ester is an ester
of a compound selected from the group consisting of Group E. And in
another example the ester is an ester of a compound selected from
the group consisting of Group F.
[0813] Another embodiment of this invention is directed to a
solvate of a compound of formula (I). And in one example the
solvate is a solvate of a compound selected from the group
consisting of Group A. And in another example the solvate is a
solvate of a compound selected from the group consisting of Group
B. And in another example the solvate is a solvate of a compound
selected from the group consisting of Group C. And in another
example the solvate is a solvate of a compound selected from the
group consisting of Group D. And in another example the solvate is
a solvate of a compound selected from the group consisting of Group
E. And in another example the solvate is a solvate of a compound
selected from the group consisting of Group F.
[0814] Another embodiment of this invention is directed to a
compound of formula (I) in isolated form. And in one example the
compound of formula (I) is selected from the group consisting of
Group A. And in one example the compound of formula (I) is selected
from the group consisting of Group D. And in one example the
compound of formula (I) is selected from the group consisting of
Group E. And in one example the compound of formula (I) is selected
from the group consisting of Group F.
[0815] Another embodiment of this invention is directed to a
compound of formula (I) in pure form. And in one example the
compound of formula (I) is selected from the group consisting of
Group A. And in one example the compound of formula (I) is selected
from the group consisting of Group D. And in one example the
compound of formula (I) is selected from the group consisting of
Group E. And in one example the compound of formula (I) is selected
from the group consisting of Group F.
[0816] Another embodiment of this invention is directed to a
compound of formula (I) in pure and isolated form. And in one
example the compound of formula (I) is selected from the group
consisting of Group A. And in one example the compound of formula
(I) is selected from the group consisting of Group D. And in one
example the compound of formula (I) is selected from the group
consisting of Group E. And in one example the compound of formula
(I) is selected from the group consisting of Group F.
[0817] Another embodiment of this invention is directed to a
pharmaceutical composition comprising an effective amount of one or
more (e.g., one) compounds of Formula (I), or a pharmaceutically
acceptable salt, solvate, or ester thereof, and one or more (e.g.,
one) pharmaceutically acceptable carriers.
[0818] Another embodiment is directed to a pharmaceutical
composition comprising an effective amount of one or more (e.g.,
one) compounds of formula (I) and a pharmaceutically acceptable
carrier.
[0819] Another embodiment is directed to a pharmaceutical
composition comprising an effective amount of a pharmaceutically
acceptable salt of one or more (e.g., one) compounds of formula (I)
and a pharmaceutically acceptable carrier.
[0820] Another embodiment is directed to a pharmaceutical
composition comprising an effective amount of a pharmaceutically
acceptable ester of one or more (e.g., one) compounds of formula
(I) and a pharmaceutically acceptable carrier.
[0821] Another embodiment is directed to a pharmaceutical
composition comprising an effective amount of a solvate of one or
more (e.g., one) compounds of formula (I) and a pharmaceutically
acceptable carrier.
[0822] Another embodiment of this invention is directed to a
pharmaceutical composition comprising an effective amount of one or
more (e.g., one) compounds of formula (I), and an effective amount
of one or more (e.g., one) other pharmaceutically active
ingredients (e.g., drugs), and a pharmaceutically acceptable
carrier. Examples of the other pharmaceutically active ingredients
include, but are not limited to drugs selected form the group
consisting of: (a) drugs useful for the treatment of Alzheimer's
disease, (b) drugs useful for inhibiting the deposition of amyloid
protein (e.g., amyloid beta protein) in, on or around neurological
tissue (e.g., the brain), (c) drugs useful for treating
neurodegenerative diseases, and (d) drugs useful for inhibiting
gamma-secretase.
[0823] Another embodiment of this invention is directed to a
pharmaceutical composition comprising a therapeutically effective
amount of one or more (e.g. one) compounds of Formula (I), or a
pharmaceutically acceptable salt, solvate, or ester thereof, and
one or more (e.g., one) pharmaceutically acceptable carriers, and
an effective amount of one or more compounds selected from the
group consisting of cholinesterase inhibitors, A.beta. antibody
inhibitors, gamma secretase inhibitors and beta secretase
inhibitors.
[0824] Another embodiment of this invention is directed to a
pharmaceutical composition comprising an effective amount of one or
more (e.g., one) compounds of formula (I), and effective amount of
one or more BACE inhibitors, and a pharmaceutically acceptable
carrier.
[0825] Another embodiment of this invention is directed to a
pharmaceutical composition comprising an effective amount of one or
more (e.g., one) compounds of formula (I), and effective amount of
one or more cholinesterase inhibitors (e.g., acetyl- and/or
butyrylchlolinesterase inhibitors), and a pharmaceutically
acceptable carrier.
[0826] Another embodiment of this invention is directed to a
pharmaceutical composition comprising an effective amount of one or
more (e.g., one) compounds of formula (I).
[0827] Another embodiment of this invention is directed to a
pharmaceutical composition comprising an effective amount of one or
more (e.g., one) compounds of formula (I), and effective amount of
one or more muscarinic antagonists (e.g., m.sub.1 agonist or
m.sub.2 antagonists), and a pharmaceutically acceptable
carrier.
[0828] Another embodiment of this invention is directed to a
pharmaceutical composition comprising an effective amount of one or
more (e.g., one) compounds of formula (I), and effective amount of
Exelon (rivastigmine), and a pharmaceutically acceptable
carrier.
[0829] Another embodiment of this invention is directed to a
pharmaceutical composition comprising an effective amount of one or
more (e.g., one) compounds of formula (I), and effective amount of
Cognex (tacrine), and a pharmaceutically acceptable carrier.
[0830] Another embodiment of this invention is directed to a
pharmaceutical composition comprising an effective amount of one or
more (e.g., one) compounds of formula (I), and effective amount of
a Tau kinase inhibitor, and a pharmaceutically acceptable
carrier.
[0831] Another embodiment of this invention is directed to a
pharmaceutical composition comprising an effective amount of one or
more (e.g., one) compounds of formula (I), and effective amount of
one or more Tau kinase inhibitor (e.g., GSK3beta inhibitor, cdk5
inhibitor, ERK inhibitor), and a pharmaceutically acceptable
carrier.
[0832] Another embodiment of this invention is directed to a
pharmaceutical composition comprising an effective amount of one or
more (e.g., one) compounds of formula (I), and effective amount of
one anti-Abeta vaccine (active immunization), and a
pharmaceutically acceptable carrier.
[0833] Another embodiment of this invention is directed to a
pharmaceutical composition comprising an effective amount of one or
more (e.g., one) compounds of formula (I), and effective amount of
one or more APP ligands, and a pharmaceutically acceptable
carrier.
[0834] Another embodiment of this invention is directed to a
pharmaceutical composition comprising an effective amount of one or
more (e.g., one) compounds of formula (I), and effective amount of
one or more agents that upregulate insulin degrading enzyme and/or
neprilysin, and a pharmaceutically acceptable carrier.
[0835] Another embodiment of this invention is directed to a
pharmaceutical composition comprising an effective amount of one or
more (e.g., one) compounds of formula (I), and effective amount of
one or more cholesterol lowering agents (for example, statins such
as Atorvastatin, Fluvastatin, Lovastatin, Mevastatin, Pitavastatin,
Pravastatin, Rosuvastatin, Simvastatin, and cholesterol absorption
inhibitor such as Ezetimibe), and a pharmaceutically acceptable
carrier.
[0836] Another embodiment of this invention is directed to a
pharmaceutical composition comprising an effective amount of one or
more (e.g., one) compounds of formula (I), and effective amount of
one or more fibrates (for example, clofibrate, Clofibride,
Etofibrate, Aluminium Clofibrate), and a pharmaceutically
acceptable carrier
[0837] Another embodiment of this invention is directed to a
pharmaceutical composition comprising an effective amount of one or
more (e.g., one) compounds of formula (I), and effective amount of
one or more LXR agonists, and a pharmaceutically acceptable
carrier.
[0838] Another embodiment of this invention is directed to a
pharmaceutical composition comprising an effective amount of one or
more (e.g., one) compounds of formula (I), and effective amount of
one or more LRP mimics, and a pharmaceutically acceptable
carrier.
[0839] Another embodiment of this invention is directed to a
pharmaceutical composition comprising an effective amount of one or
more (e.g., one) compounds of formula (I), and effective amount of
one or more 5-HT6 receptor antagonists, and a pharmaceutically
acceptable carrier.
[0840] Another embodiment of this invention is directed to a
pharmaceutical composition comprising an effective amount of one or
more (e.g., one) compounds of formula (I), and effective amount of
one or more nicotinic receptor agonists, and a pharmaceutically
acceptable carrier.
[0841] Another embodiment of this invention is directed to a
pharmaceutical composition comprising an effective amount of one or
more (e.g., one) compounds of formula (I), and effective amount of
one or more H3 receptor antagonists, and a pharmaceutically
acceptable carrier.
[0842] Another embodiment of this invention is directed to a
pharmaceutical composition comprising an effective amount of one or
more (e.g., one) compounds of formula (I), and effective amount of
one or more histone deacetylase inhibitors, and a pharmaceutically
acceptable carrier.
[0843] Another embodiment of this invention is directed to a
pharmaceutical composition comprising an effective amount of one or
more (e.g., one) compounds of formula (I), and effective amount of
one or more hsp90 inhibitors, and a pharmaceutically acceptable
carrier.
[0844] Another embodiment of this invention is directed to a
pharmaceutical composition comprising an effective amount of one or
more (e.g., one) compounds of formula (I), and effective amount of
one or more ml muscarinic receptor agonists, and a pharmaceutically
acceptable carrier.
[0845] Another embodiment of this invention is directed to
combinations, i.e., a pharmaceutical composition, comprising a
pharmaceutically acceptable carrier, an effective (i.e.,
therapeutically effective) amount of one or more compounds of
formula (I), in combination with an effective (i.e.,
therapeutically effective) amount of one or more compounds selected
from the group consisting of cholinesterase inhibitors (such as,
for example,
(.+-.)-2,3-dihydro-5,6-dimethoxy-2-[[1-(phenylmethyl)-4-piperidinyl]methy-
l]-1H-inden-1-one hydrochloride, i.e., donepezil hydrochloride,
available as the Aricept' brand of donepezil hydrochloride),
A.beta. antibody inhibitors, gamma secretase inhibitors and beta
secretase inhibitors.
[0846] Another embodiment of this invention is directed to a
pharmaceutical composition comprising an effective amount of one or
more (e.g., one) compounds of formula (I), and effective amount of
one or more 5-HT6 receptor antagonists mGluR1 or mGluR5 positive
allosteric modulators or agonists, and a pharmaceutically
acceptable carrier.
[0847] Another embodiment of this invention is directed to a
pharmaceutical composition comprising an effective amount of one or
more (e.g., one) compounds of formula (I), and effective amount of
one or more one mGluR2/3 antagonists, and a pharmaceutically
acceptable carrier.
[0848] Another embodiment of this invention is directed to a
pharmaceutical composition comprising an effective amount of one or
more (e.g., one) compounds of formula (I), and effective amount of
one or more anti-inflammatory agents that can reduce
neuroinflammation, and a pharmaceutically acceptable carrier.
[0849] Another embodiment of this invention is directed to a
pharmaceutical composition comprising an effective amount of one or
more (e.g., one) compounds of formula (I), and effective amount of
one or more Prostaglandin EP2 receptor antagonists, and a
pharmaceutically acceptable carrier.
[0850] Another embodiment of this invention is directed to a
pharmaceutical composition comprising an effective amount of one or
more (e.g., one) compounds of formula (I), and effective amount of
one or more PAM inhibitors, and a pharmaceutically acceptable
carrier.
[0851] Another embodiment of this invention is directed to a
pharmaceutical composition comprising an effective amount of one or
more (e.g., one) compounds of formula (I), and effective amount of
one or more agents that can induce Abeta efflux such as gelsolin,
and a pharmaceutically acceptable carrier.
[0852] Other embodiments of this invention are directed to any one
of the above embodiments directed to pharmaceutical compositions
wherein the compound of formula (I) is selected from the group
consisting of Group A.
[0853] Other embodiments of this invention are directed to any one
of the above embodiments directed to pharmaceutical compositions
wherein the compound of formula (I) is selected from the group
consisting of Group B.
[0854] Other embodiments of this invention are directed to any one
of the above embodiments directed to pharmaceutical compositions
wherein the compound of formula (I) is selected from the group
consisting of Group C.
[0855] Other embodiments of this invention are directed to any one
of the above embodiments directed to pharmaceutical compositions
wherein the compound of formula (I) is selected from the group
consisting of Group D.
[0856] Other embodiments of this invention are directed to any one
of the above embodiments directed to pharmaceutical compositions
wherein the compound of formula (I) is selected from the group
consisting of Group E.
[0857] Other embodiments of this invention are directed to any one
of the above embodiments directed to pharmaceutical compositions
wherein the compound of formula (I) is selected from the group
consisting of Group F.
[0858] The compounds of formula (I) can be useful as gamma
secretase modulators and can be useful in the treatment and
prevention of diseases such as, for example, central nervous system
disorders (such as Alzheimers disease and Downs Syndrome), mild
cognitive impairment, glaucoma, cerebral amyloid angiopathy,
stroke, dementia, microgliosis, brain inflammation, and olfactory
function loss.
[0859] Another embodiment of this invention is directed to a method
of treating a central nervous system disorder comprising
administering a therapeutically effective amount of at least one
compound of formula (I) to a patient in need of such treatment.
[0860] Another embodiment of this invention is directed to a method
of treating a central nervous system disorder comprising
administering a therapeutically effective amount of a
pharmaceutical composition comprising a therapeutically effective
amount of at least one compound of formula (I), or a
pharmaceutically acceptable salt, solvate, or ester thereof, and at
least one pharmaceutically acceptable carrier.
[0861] Another embodiment of this invention is directed to a method
of treating a central nervous system disorder comprising
administering a therapeutically effective amount of a
pharmaceutical composition comprising a therapeutically effective
amount of at least one compound of formula (I), or a
pharmaceutically acceptable salt, solvate, or ester thereof, and at
least one pharmaceutically acceptable carrier, and a
therapeutically effective amount of one or more compounds selected
from the group consisting of cholinesterase inhibitors, A.beta.
antibody inhibitors, gamma secretase inhibitors and beta secretase
inhibitors.
[0862] Thus, another embodiment of this invention is directed to a
method for modulating (including inhibiting, antagonizing and the
like) gamma-secretase comprising administering an effective (i.e.,
therapeutically effective) amount of one or more (e.g., one)
compounds of formula (I) to a patient in need of such
treatment.
[0863] Another embodiment of this invention is directed to a method
for modulating (including inhibiting, antagonizing and the like)
gamma-secretase, comprising administering an effective (i.e.,
therapeutically effective) amount of a compound of formula (I) to a
patient in need of treatment.
[0864] Another embodiment of this invention is directed to a method
of treating one or more neurodegenerative diseases, comprising
administering an effective (i.e., therapeutically effective) amount
of one or more (e.g., one) compounds of formula (I) to a patient in
need of treatment.
[0865] Another embodiment of this invention is directed to a method
of treating one or more neurodegenerative diseases, comprising
administering an effective (i.e., therapeutically effective) amount
of a compound of formula (I) to a patient in need of treatment.
[0866] Another embodiment of this invention is directed to a method
of inhibiting the deposition of amyloid protein (e.g., amyloid beta
protein) in, on or around neurological tissue (e.g., the brain),
comprising administering an effective (i.e., therapeutically
effective) amount of one or more (e.g., one) compounds of formula
(I) to a patient in need of treatment.
[0867] Another embodiment of this invention is directed to a method
of inhibiting the deposition of amyloid protein (e.g., amyloid beta
protein) in, on or around neurological tissue (e.g., the brain),
comprising administering an effective (i.e., therapeutically
effective) amount of a compound of formula (I) to a patient in need
of treatment.
[0868] Another embodiment of this invention is directed to a method
of treating Alzheimer's disease, comprising administering an
effective (i.e., therapeutically effective) amount of one or more
(e.g., one) compounds of formula (I) to a patient in need of
treatment.
[0869] Another embodiment of this invention is directed to a method
of treating Alzheimer's disease, comprising administering an
effective (i.e., therapeutically effective) amount of a compound of
formula (I) to a patient in need of treatment.
[0870] Another embodiment of this invention is directed to a method
of treating Alzheimer's disease, comprising administering an
effective (i.e., therapeutically effective) amount of a compound of
formula (I) to a patient in need of treatment.
[0871] Another embodiment of this invention is directed to a method
of treating mild cognitive impairment, glaucoma, cerebral amyloid
angiopathy, stroke, dementia, microgliosis, brain inflammation, or
olfactory function loss, comprising administering an effective
(i.e., therapeutically effective) amount of one or more (e.g., one)
compounds of formula (I) to a patient in need of treatment.
[0872] Another embodiment of this invention is directed to a method
of treating mild cognitive impairment, glaucoma, cerebral amyloid
angiopathy, stroke, dementia, microgliosis, brain inflammation, or
olfactory function loss, comprising administering an effective
(i.e., therapeutically effective) amount of a compound of formula
(I) to a patient in need of treatment.
[0873] Another embodiment of this invention is directed to a method
of treating mild cognitive impairment, comprising administering an
effective amount of one or more (e.g., one) compounds of formula
(I) to a patient in need of treatment.
[0874] Another embodiment of this invention is directed to a method
of treating glaucoma, comprising administering an effective amount
of one or more (e.g., one) compounds of formula (I) to a patient in
need of treatment.
[0875] Another embodiment of this invention is directed to a method
of treating cerebral amyloid angiopathy, comprising administering
an effective amount of one or more (e.g., one) compounds of formula
(I) to a patient in need of treatment.
[0876] Another embodiment of this invention is directed to a method
of treating stroke, comprising administering an effective amount of
one or more (e.g., one) compounds of formula (I) to a patient in
need of treatment.
[0877] Another embodiment of this invention is directed to a method
of treating dementia, comprising administering an effective amount
of one or more (e.g., one) compounds of formula (I) to a patient in
need of treatment.
[0878] Another embodiment of this invention is directed to a method
of treating microgliosis, comprising administering an effective
amount of one or more (e.g., one) compounds of formula (I) to a
patient in need of treatment.
[0879] Another embodiment of this invention is directed to a method
of treating brain inflammation, comprising administering an
effective amount of one or more (e.g., one) compounds of formula
(I) to a patient in need of treatment.
[0880] Another embodiment of this invention is directed to a method
of treating olfactory function loss, comprising administering an
effective amount of one or more (e.g., one) compounds of formula
(I) to a patient in need of treatment.
[0881] Another embodiment of this invention is directed to a method
of treating Downs syndrome, comprising administering an effective
amount of one or more (e.g., one) compounds of formula (I) to a
patient in need of treatment.
[0882] Another embodiment of this invention is directed to a method
of treating Downs syndrome, comprising administering an effective
amount of a compound of formula (I) to a patient in need of
treatment.
[0883] Other embodiments of this invention are directed to any one
of the above embodiments directed to methods of treating wherein
the compound of formula (I) is selected from the group consisting
of Group A.
[0884] Other embodiments of this invention are directed to any one
of the above embodiments directed to methods of treating wherein
the compound of formula (I) is selected from the group consisting
of Group B.
[0885] Other embodiments of this invention are directed to any one
of the above embodiments directed to methods of treating wherein
the compound of formula (I) is selected from the group consisting
of Group C.
[0886] Other embodiments of this invention are directed to any one
of the above embodiments directed to methods of treating wherein
the compound of formula (I) is selected from the group consisting
of Group D.
[0887] Other embodiments of this invention are directed to any one
of the above embodiments directed to methods of treating wherein
the compound of formula (I) is selected from the group consisting
of Group E.
[0888] Other embodiments of this invention are directed to any one
of the above embodiments directed to methods of treating wherein
the compound of formula (I) is selected from the group consisting
of Group F.
[0889] This invention also provides combination therapies for (1)
modulating gamma-secretase, or (2) treating one or more
neurodegenerative diseases, or (3) inhibiting the deposition of
amyloid protein (e.g., amyloid beta protein) in, on or around
neurological tissue (e.g., the brain), or (4) treating Alzheimer's
disease. The combination therapies are directed to methods
comprising the administration of one or more (e.g. one) compounds
of formula (I) and the administration of one or more (e.g., one)
other pharmaceutical active ingredients (e.g., drugs). The
compounds of formula (I) and the other drugs can be administered
separately (i.e., each is in its own separate dosage form), or the
compounds of formula (I) can be combined with the other drugs in
the same dosage form.
[0890] Thus, other embodiments of this invention are directed to
any one of the methods of treatment, or methods of inhibiting,
described herein, wherein an effective amount of the compound of
formula (I) is used in combination with an effective amount of one
or more other pharmaceutically active ingredients (e.g., drugs).
The other pharmaceutically active ingredients (i.e., drugs) are
selected from the group consisting of: RACE inhibitors (beta
secretase inhibitors), muscarinic antagonists (e.g., m.sub.1
agonists or m.sub.2 antagonists), cholinesterase inhibitors (e.g.,
acetyl- and/or butyrylchlolinesterase inhibitors); gamma secretase
inhibitors; gamma secretase modulators; HMG-CoA reductase
inhibitors; non-steroidal anti-inflammatory agents;
N-methyl-D-aspartate receptor antagonists; anti-amyloid antibodies;
vitamin E; nicotinic acetylcholine receptor agonists; CB1 receptor
inverse agonists or CB1 receptor antagonists; an antibiotic; growth
hormone secretagogues; histamine H3 antagonists; AMPA agonists;
PDE4 inhibitors; GABA.sub.A inverse agonists; inhibitors of amyloid
aggregation; glycogen synthase kinase beta inhibitors; promoters of
alpha secretase activity; PDE-10 inhibitors; Exelon (rivastigmine);
Cognex (tacrine); Tau kinase inhibitors (e.g., GSK3beta inhibitors,
cdk5 inhibitors, or ERK inhibitors); anti-Abeta vaccine; APP
ligands; agents that upregulate insulin cholesterol lowering agents
(for example, statins such as Atorvastatin, Fluvastatin,
Lovastatin, Mevastatin, Pitavastatin, Pravastatin, Rosuvastatin,
Simvastatin); cholesterol absorption inhibitors (such as
Ezetimibe); fibrates (such as, for example, for example,
clofibrate, Clofibride, Etofibrate, and Aluminium Clofibrate); LXR
agonists; LRP mimics; nicotinic receptor agonists; H3 receptor
antagonists; histone deacetylase inhibitors; hsp90 inhibitors; ml
muscarinic receptor agonists; 5-HT6 receptor antagonists; mGluR1;
mGluR5; positive allosteric modulators or agonists; mGluR2/3
antagonists; anti-inflammatory agents that can reduce
neuroinflammation; Prostaglandin EP2 receptor antagonists; PAI-1
inhibitors; and agents that can induce Abeta efflux such as
gelsolin.
[0891] Other embodiments of this invention are directed to any one
of the methods of treatment, or methods of inhibiting, described
herein, wherein the compound of formula (I) is used in combination
with an effective amount of one or more other pharmaceutically
active ingredients selected from the group consisting of: BACE
inhibitors (beta secretase inhibitors), muscarinic antagonists
(e.g., m.sub.1 agonist or m.sub.2 antagonists), cholinesterase
inhibitors (e.g., acetyl- and/or butyrylchlolinesterase
inhibitors); gamma secretase inhibitors; gamma secretase
modulators; HMG-CoA reductase inhibitors; non-steroidal
anti-inflammatory agents; N-methyl-D-aspartate receptor
antagonists; anti-amyloid antibodies; vitamin E; nicotinic
acetylcholine receptor agonists; CB1 receptor inverse agonists or
CB1 receptor antagonists; an antibiotic; growth hormone
secretagogues; histamine H3 antagonists; AMPA agonists; PDE4
inhibitors; GABA.sub.A inverse agonists; inhibitors of amyloid
aggregation; glycogen synthase kinase beta inhibitors; promoters of
alpha secretase activity; PDE-10 inhibitors and cholesterol
absorption inhibitors (e.g., ezetimibe).
[0892] Another embodiment of this invention is directed to a method
of treating Alzheimer's disease, comprising administering an
effective (i.e., therapeutically effective) amount of one or more
(e.g., one) compounds of formula (I), in combination with an
effective (i.e., therapeutically effective) amount of one or more
cholinesterase inhibitors (such as, for example,
(.+-.)-2,3-dihydro-5,6-dimethoxy-2-[[1-(phenylmethyl)-4-piperidinyl]methy-
l]-1H-inden-1-one hydrochloride, i.e., donepezil hydrochloride,
available as the Aricept.RTM. brand of donepezil hydrochloride), to
a patient in need of treatment.
[0893] Another embodiment of this invention is directed to a method
of treating Alzheimer's disease, comprising administering an
effective (i.e., therapeutically effective) amount of a compound of
formula (I), in combination with an effective (i.e.,
therapeutically effective) amount of one or more (e.g., one)
cholinesterase inhibitors (such as, for example,
(.+-.)-2,3-dihydro-5,6-dimethoxy-2-[[1-(phenylmethyl)-4-piperidinyl]methy-
l]-1H-inden-1-one hydrochloride, i.e., donepezil hydrochloride,
available as the Aricept.RTM. brand of donepezil hydrochloride), to
a patient in need of treatment.
[0894] Another embodiment of this invention is directed to a method
of treating Alzheimer's disease, comprising administering an
effective (i.e., therapeutically effective) amount of one or more
(e.g., one) compounds of formula (I), in combination with an
effective (i.e., therapeutically effective) amount of one or more
compounds selected from the group consisting of A.beta. antibody
inhibitors, gamma secretase inhibitors and beta secretase
inhibitors.
[0895] Another embodiment of this invention is directed to a method
of treating Alzheimer's disease, comprising administering an
effective (i.e., therapeutically effective) amount of one or more
(e.g., one) compounds of formula (I), in combination with an
effective (i.e., therapeutically effective) amount of one or more
BACE inhibitors.
[0896] Another embodiment of this invention is directed to a method
of treating Alzheimer's disease, comprising administering an
effective amount of one or more compounds of formula (I), in
combination with an effective amount of Exelon (rivastigmine).
[0897] Another embodiment of this invention is directed to a method
of treating Alzheimer's disease, comprising administering an
effective amount of one or more compounds of formula (I), in
combination with an effective amount of Cognex (tacrine).
[0898] Another embodiment of this invention is directed to a method
of treating Alzheimer's disease, comprising administering an
effective amount of one or more compounds of formula (I), in
combination with an effective amount of a Tau kinase inhibitor.
[0899] Another embodiment of this invention is directed to a method
of treating Alzheimer's disease, comprising administering an
effective amount of one or more compounds of formula (I), in
combination with an effective amount of one or more Tau kinase
inhibitor (e.g., GSK3beta inhibitor, cdk5 inhibitor, ERK
inhibitor).
[0900] This invention also provides a method of treating
Alzheimer's disease, comprising administering an effective amount
of one or more compounds of formula (I), in combination with an
effective amount of one anti-Abeta vaccination (active
immunization).
[0901] Another embodiment of this invention is directed to a method
of treating Alzheimer's disease, comprising administering an
effective amount of one or more compounds of formula (I), in
combination with an effective amount of one or more APP
ligands.
[0902] Another embodiment of this invention is directed to a method
of treating Alzheimer's disease, comprising administering an
effective amount of one or more compounds of formula (I), in
combination with an effective amount of one or more agents that
upregulate insulin degrading enzyme and/or neprilysin.
[0903] Another embodiment of this invention is directed to a method
of treating Alzheimer's disease, comprising administering an
effective amount of one or more compounds of formula (I), in
combination with an effective amount of one or more cholesterol
lowering agents (for example, statins such as Atorvastatin,
Fluvastatin, Lovastatin, Mevastatin, Pitavastatin, Pravastatin,
Rosuvastatin, Simvastatin, and cholesterol absorption inhibitor
such as Ezetimibe).
[0904] This invention also provides a method of treating
Alzheimer's disease, comprising administering an effective amount
of one or more compounds of formula (I), in combination with an
effective amount of one or more fibrates (for example, clofibrate,
Clofibride, Etofibrate, Aluminium Clofibrate).
[0905] Another embodiment of this invention is directed to a method
of treating Alzheimer's disease, comprising administering an
effective amount of one or more compounds of formula (I), in
combination with an effective amount of one or more LXR
agonists.
[0906] Another embodiment of this invention is directed to a method
of treating Alzheimer's disease, comprising administering an
effective amount of one or more compounds of formula (I), in
combination with an effective amount of one or more LRP mimics.
[0907] Another embodiment of this invention is directed to a method
of treating Alzheimer's disease, comprising administering an
effective amount of one or more compounds of formula (I), in
combination with an effective amount of one or more 5-HT6 receptor
antagonists.
[0908] Another embodiment of this invention is directed to a method
of treating Alzheimer's disease, comprising administering an
effective amount of one or more compounds of formula (I), in
combination with an effective amount of one or more nicotinic
receptor agonists.
[0909] Another embodiment of this invention is directed to a method
of treating Alzheimer's disease, comprising administering an
effective amount of one or more compounds of formula (I), in
combination with an effective amount of one or more H3 receptor
antagonists.
[0910] This invention also provides a method of treating
Alzheimer's disease, comprising administering an effective amount
of one or more compounds of formula (I), in combination with an
effective amount of one or more histone deacetylase inhibitors.
[0911] Another embodiment of this invention is directed to a method
of treating Alzheimer's disease, comprising administering an
effective amount of one or more compounds of formula (I), in
combination with an effective amount of one or more hsp90
inhibitors.
[0912] Another embodiment of this invention is directed to a method
of treating Alzheimer's disease, comprising administering an
effective amount of one or more compounds of formula (I), in
combination with an effective amount of one or more ml muscarinic
receptor agonists.
[0913] Another embodiment of this invention is directed to a method
of treating Alzheimer's disease, comprising administering an
effective amount of one or more compounds of formula (I), in
combination with an effective amount of one or more 5-HT6 receptor
antagonists mGluR1 or mGluR5 positive allosteric modulators or
agonists.
[0914] Another embodiment of this invention is directed to a method
of treating Alzheimer's disease, comprising administering an
effective amount of one or more compounds of formula (I), in
combination with an effective amount of one or more mGluR2/3
antagonists.
[0915] Another embodiment of this invention is directed to a method
of treating Alzheimer's disease, comprising administering an
effective amount of one or more compounds of formula (I), in
combination with an effective amount of one or more
anti-inflammatory agents that can reduce neuroinflammation.
[0916] Another embodiment of this invention is directed to a method
of treating Alzheimer's disease, comprising administering an
effective amount of one or more compounds of formula (I), in
combination with an effective amount of one or more Prostaglandin
EP2 receptor antagonists.
[0917] Another embodiment of this invention is directed to a method
of treating Alzheimer's disease, comprising administering an
effective amount of one or more compounds of formula (I), in
combination with an effective amount of one or more PAI-1
inhibitors.
[0918] Another embodiment of this invention is directed to a method
of treating Alzheimer's disease, comprising administering an
effective amount of one or more compounds of formula (I), in
combination with an effective amount of one or more agents that can
induce Abeta efflux such as gelsolin.
[0919] Another embodiment of this invention is directed to a method
of treating Downs syndrome, comprising administering an effective
(i.e., therapeutically effective) amount of one or more (e.g., one)
compounds of formula (I) to a patient in need of treatment.
[0920] Another embodiment of this invention is directed to a method
of treating Downs syndrome, comprising administering an effective
(i.e., therapeutically effective) amount of a compound of formula
(I) to a patient in need of treatment.
[0921] Another embodiment of this invention is directed to a method
of treating Downs syndrome, comprising administering an effective
(i.e., therapeutically effective) amount of one or more (e.g., one)
compounds of formula (I), in combination with an effective (i.e.,
therapeutically effective) amount of one or more cholinesterase
inhibitors (such as, for example,
(.+-.)-2,3-dihydro-5,6-dimethoxy-2-[[1-(phenylmethyl)-4-piperidi-
nyl]methyl]-1H-inden-1-one hydrochloride, i.e., donepezil
hydrochloride, available as the Aricept.RTM. brand of donepezil
hydrochloride), to a patient in need of treatment.
[0922] Another embodiment of this invention is directed to a method
of treating Downs syndrome, comprising administering an effective
(i.e., therapeutically effective) amount of a compound of formula
(I), in combination with an effective (i.e., therapeutically
effective) amount of one or more (e.g., one) cholinesterase
inhibitors (such as, for example,
(.+-.)-2,3-dihydro-5,6-dimethoxy-2-[[1-(phenylmethyl)-4-piperidinyl]methy-
l]-1H-inden-1-one hydrochloride, i.e., donepezil hydrochloride,
available as the Aricept.RTM. brand of donepezil hydrochloride), to
a patient in need of treatment.
[0923] Another embodiment of this invention is directed to
combinations (i.e., pharmaceutical compositions) comprising an
effective (i.e., therapeutically effective) amount of one or more
(e.g., one) compounds of formula (I), in combination with an
effective (i.e., therapeutically effective) amount of one or more
compounds selected from the group consisting of cholinesterase
inhibitors (such as, for example,
(.+-.)-2,3-dihydro-5,6-dimethoxy-2-[[1-(phenylmethyl)-4-piperidinyl]methy-
l]-1H-inden-1-one hydrochloride, i.e., donepezil hydrochloride,
available as the Aricept.RTM. brand of donepezil hydrochloride),
A.beta. antibody inhibitors, gamma secretase inhibitors and beta
secretase inhibitors. The pharmaceutical compositions also comprise
a pharmaceutically acceptable carrier.
[0924] Other embodiments of this invention are directed to any one
of the above embodiments directed to combination therapies (i.e.,
the above methods of treating wherein compounds of formula (I) are
used in combination with other pharmaceutically active ingredients,
i.e., drugs) wherein the compound of formula (I) is selected from
the group consisting of Group A.
[0925] Other embodiments of this invention are directed to any one
of the above embodiments directed to combination therapies (i.e.,
the above methods of treating wherein compounds of formula (I) are
used in combination with other pharmaceutically active ingredients,
i.e., drugs) wherein the compound of formula (I) is selected from
the group consisting of Group B.
[0926] Other embodiments of this invention are directed to any one
of the above embodiments directed to combination therapies (i.e.,
the above methods of treating wherein compounds of formula (I) are
used in combination with other pharmaceutically active ingredients,
i.e., drugs) wherein the compound of formula (I) is selected from
the group consisting of Group C.
[0927] Other embodiments of this invention are directed to any one
of the above embodiments directed to combination therapies (i.e.,
the above methods of treating wherein compounds of formula (I) are
used in combination with other pharmaceutically active ingredients,
i.e., drugs) wherein the compound of formula (I) is selected from
the group consisting of Group D.
[0928] Other embodiments of this invention are directed to any one
of the above embodiments directed to combination therapies (i.e.,
the above methods of treating wherein compounds of formula (I) are
used in combination with other pharmaceutically active ingredients,
i.e., drugs) wherein the compound of formula (I) is selected from
the group consisting of Group E.
[0929] Other embodiments of this invention are directed to any one
of the above embodiments directed to combination therapies (i.e.,
the above methods of treating wherein compounds of formula (I) are
used in combination with other pharmaceutically active ingredients,
i.e., drugs) wherein the compound of formula (I) is selected from
the group consisting of Group F.
[0930] Another embodiment of this invention is directed to a kit
comprising, in separate containers, in a single package,
pharmaceutical compositions for use in combination, wherein one
container comprises an effective amount of a compound of formula
(I) in a pharmaceutically acceptable carrier, and another container
(i.e., a second container) comprises an effective amount of another
pharmaceutically active ingredient (as described above), the
combined quantities of the compound of formula (I) and the other
pharmaceutically active ingredient being effective to: (a) treat
Alzheimer's disease, or (b) inhibit the deposition of amyloid
protein (e.g., amyloid beta protein) in, on or around neurological
tissue (e.g., the brain), or (c) treat neurodegenerative diseases,
or (d) modulate the activity of gamma-secretase, or (e) mild
cognitive impairment, or (f) glaucoma, or (g) cerebral amyloid
angiopathy, or (h) stroke, or (i) dementia, or (j) microgliosis, or
(k) brain inflammation, or (l) olfactory function loss.
[0931] Another embodiment of this invention is directed to a kit
comprising, in separate containers, in a single package,
pharmaceutical compositions for use in combination, wherein one
container comprises an effective amount of one or more (e.g., one)
compounds of formula (I) in a pharmaceutically acceptable carrier,
and another container (i.e., a second container) comprises an
effective amount of another pharmaceutically active ingredient (as
described above), the combined quantities of the compounds of
formula (I) and the other pharmaceutically active ingredient being
effective to: (a) treat Alzheimer's disease, or (b) inhibit the
deposition of amyloid protein (e.g., amyloid beta protein) in, on
or around neurological tissue (e.g., the brain), or (c) treat
neurodegenerative diseases, or (d) modulate the activity of
gamma-secretase.
[0932] Another embodiment of this invention is directed to a kit
comprising, in separate containers, in a single package,
pharmaceutical compositions for use in combination, wherein one
container comprises an effective amount of a compound of formula
(I) in a pharmaceutically acceptable carrier, and another container
(i.e., a second container) comprises an effective amount of another
pharmaceutically active ingredient (as described above), the
combined quantities of the compound of formula (I) and the other
pharmaceutically active ingredient being effective to: (a) treat
Alzheimer's disease, or (b) inhibit the deposition of amyloid
protein (e.g., amyloid beta protein) in, on or around neurological
tissue (e.g., the brain), or (c) treat neurodegenerative diseases,
or (d) modulate the activity of gamma-secretase.
[0933] Other embodiments of this invention are directed to any one
of the above embodiments directed to kits wherein the compound of
formula (I) is selected from the group consisting of Group A.
[0934] Other embodiments of this invention are directed to any one
of the above embodiments directed to kits wherein the compound of
formula (I) is selected from the group consisting of Group B.
[0935] Other embodiments of this invention are directed to any one
of the above embodiments directed to kits wherein the compound of
formula (I) is selected from the group consisting of Group C.
[0936] Other embodiments of this invention are directed to any one
of the above embodiments directed to kits wherein the compound of
formula (I) is selected from the group consisting of Group D.
[0937] Other embodiments of this invention are directed to any one
of the above embodiments directed to kits wherein the compound of
formula (I) is selected from the group consisting of Group E.
[0938] Other embodiments of this invention are directed to any one
of the above embodiments directed to kits wherein the compound of
formula (I) is selected from the group consisting of Group F.
[0939] Examples of cholinesterase inhibitors are tacrine,
donepezil, rivastigmine, galantamine, pyridostigmine and
neostigmine, with tacrine, donepezil, rivastigmine and galantamine
being preferred.
[0940] Examples of m.sub.1 agonists are known in the art. Examples
of m.sub.2 antagonists are also known in the art; in particular,
m.sub.2 antagonists are disclosed in U.S. Pat. Nos. 5,883,096;
6,037,352; 5,889,006; 6,043,255; 5,952,349; 5,935,958; 6,066,636;
5,977,138; 6,294,554; 6,043,255; and 6,458,812; and in WO
03/031412, all of which are incorporated herein by reference.
[0941] Examples of BACE inhibitors include those described in:
US2005/0119227 published Jun. 2, 2005 (see also WO2005/016876
published Feb. 24, 2005), US2005/0043290 published Feb. 24, 2005
(see also WO2005/014540 published Feb. 17, 2005), WO2005/058311
published Jun. 30, 2005 (see also US2007/0072852 published Mar. 29,
2007), US2006/0111370 published May 25, 2006 (see also
WO2006/065277 published Jun. 22, 2006), U.S. application Ser. No.
11/710,582 filed Feb. 23, 2007, US2006/0040994 published Feb. 23,
2006 (see also WO2006/014762 published Feb. 9, 2006), WO2006/014944
published Feb. 9, 2006 (see also US2006/0040948 published Feb. 23,
2006), WO2006/138266 published Dec. 28, 2006 (see also
US2007/0010667 published Jan. 11, 2007), WO2006/138265 published
Dec. 28, 2006, WO2006/138230 published Dec. 28, 2006, WO2006/138195
published Dec. 28, 2006 (see also US2006/0281729 published Dec. 14,
2006), WO2006/138264 published Dec. 28, 2006 (see also
US2007/0060575 published Mar. 15, 2007), WO2006/138192 published
Dec. 28, 2006 (see also US2006/0281730 published Dec. 14, 2006),
WO2006/138217 published Dec. 28, 2006 (see also US2006/0287294
published Dec. 21, 2006), US2007/0099898 published May 3, 200 (see
also WO2007/050721 published May 3, 2007), WO2007/053506 published
May 10, 2007 (see also US2007/099875 published May 3, 2007), U.S.
application Ser. No. 11/759,336 filed Jun. 7, 2007, U.S.
Application Ser. No. 60/874,362 filed Dec. 12, 2006, and U.S.
Application Ser. No. 60/874,419 filed Dec. 12, 2006, the
disclosures of each being incorporated herein by reference
thereto.
[0942] It is noted that the carbons of formula (I) and other
formulas herein may be replaced with 1 to 3 silicon atoms so long
as all valency requirements are satisfied.
[0943] As used above, and throughout this disclosure, the following
terms, unless otherwise indicated, shall be understood to have the
following meanings:
[0944] "Patient" includes both human and animals.
[0945] "Mammal" means humans and other mammalian animals.
[0946] "One or more" means that there is at least one and there can
be more than one, and examples include 1, 2 or 3, or 1 and 2, or
1.
[0947] "At least one" means there is at least one and there can be
more than one, and examples include 1, 2 or 3, or 1 and 2, or
1.
[0948] "Bn" means benzyl.
[0949] "CAN" means ceric ammonium nitrate.
[0950] "EDCI" means (3-(dimethylamino)propyl)ethyl carbodiimide
hydrochloride.
[0951] "Et" means ethyl.
[0952] "HOBT" means 1-hydroxybenzotriazole.
[0953] "i-pr" means isopropyl.
[0954] "Me" means methyl.
[0955] "PMB" means p-methoxybenzyl.
[0956] "PMBO" means p-methoxybenzyloxy.
[0957] "Pr" means propyl.
[0958] "PTSA" means p-toluene sulfonic acid.
[0959] "t-Bu" means tert-butyl.
[0960] "Fused benzocycloalkyl ring" means a phenyl ring fused to a
cycloalkyl ring (as cycloalkyl is defined below), such as, for
example,
##STR00211##
[0961] "Alkyl" means an aliphatic hydrocarbon group which may be
straight or branched and comprising about 1 to about 20 carbon
atoms in the chain. Preferred alkyl groups contain about 1 to about
12 carbon atoms in the chain. More preferred alkyl groups contain
about 1 to about 6 carbon atoms in the chain. Branched means that
one or more lower alkyl groups such as methyl, ethyl or propyl, are
attached to a linear alkyl chain. "Lower alkyl" means a group
having about 1 to about 6 carbon atoms in the chain which may be
straight or branched. "Alkyl" may be unsubstituted or optionally
substituted by one or more substituents which may be the same or
different, each substituent being independently selected from the
group consisting of halo, alkyl, aryl, cycloalkyl, cyano, hydroxy,
alkoxy, alkylthio, amino, oxime (e.g., .dbd.N--ON), --NH(alkyl),
--NH(cycloalkyl), --N(alkyl).sub.2, --O--C(O)-alkyl,
--O--C(O)-aryl, --O--C(O)-cycloalkyl, carboxy and --C(O)O-alkyl.
Non-limiting examples of suitable alkyl groups include methyl,
ethyl, n-propyl, isopropyl and t-butyl.
[0962] "Alkenyl" means an aliphatic hydrocarbon group containing at
least one carbon-carbon double bond and which may be straight or
branched and comprising about 2 to about 15 carbon atoms in the
chain. Preferred alkenyl groups have about 2 to about 12 carbon
atoms in the chain; and more preferably about 2 to about 6 carbon
atoms in the chain. Branched means that one or more lower alkyl
groups such as methyl, ethyl or propyl, are attached to a linear
alkenyl chain. "Lower alkenyl" means about 2 to about 6 carbon
atoms in the chain which may be straight or branched. "Alkenyl" may
be unsubstituted or optionally substituted by one or more
substituents which may be the same or different, each substituent
being independently selected from the group consisting of halo,
alkyl. aryl, cycloalkyl, cyano, alkoxy and --S(alkyl), Non-limiting
examples of suitable alkenyl groups include ethenyl, propenyl,
n-butenyl, 3-methylbut-2-enyl, n-pentenyl, octenyl and decenyl.
[0963] "Alkylene" means a difunctional group obtained by removal of
a hydrogen atom from an alkyl group that is defined above.
Non-limiting examples of alkylene include methylene, ethylene and
propylene.
[0964] "Alkynyl" means an aliphatic hydrocarbon group containing at
least one carbon-carbon triple bond and which may be straight or
branched and comprising about 2 to about 15 carbon atoms in the
chain. Preferred alkynyl groups have about 2 to about 12 carbon
atoms in the chain; and more preferably about 2 to about 4 carbon
atoms in the chain. Branched means that one or more lower alkyl
groups such as methyl, ethyl or propyl, are attached to a linear
alkynyl chain. "Lower alkynyl" means about 2 to about 6 carbon
atoms in the chain which may be straight or branched. Non-limiting
examples of suitable alkynyl groups include ethynyl, propynyl,
2-butynyl and 3-methylbutynyl. "Alkynyl" may be unsubstituted or
optionally substituted by one or more substituents which may be the
same or different, each substituent being independently selected
from the group consisting of alkyl, aryl and cycloalkyl.
[0965] "Aryl" means an aromatic monocyclic or multicyclic ring
system comprising about 6 to about 14 carbon atoms, preferably
about 6 to about 10 carbon atoms. The aryl group can be optionally
substituted with one or more "ring system substituents" which may
be the same or different, and are as defined herein. Non-limiting
examples of suitable aryl groups include phenyl and naphthyl.
[0966] "Heteroaryl" means an aromatic monocyclic or multicyclic
ring system comprising about 5 to about 14 ring atoms, preferably
about 5 to about 10 ring atoms, in which one or more of the ring
atoms is an element other than carbon, for example nitrogen, oxygen
or sulfur, alone or in combination. Preferred heteroaryls contain
about 5 to about 6 ring atoms. The "heteroaryl" can be optionally
substituted by one or more "ring system substituents" which may be
the same or different, and are as defined herein. The prefix aza,
oxa or thia before the heteroaryl root name means that at least a
nitrogen, oxygen or sulfur atom respectively, is present as a ring
atom. A nitrogen atom of a heteroaryl can be optionally oxidized to
the corresponding N-oxide. "Heteroaryl" may also include a
heteroaryl as defined above fused to an aryl as defined above.
Non-limiting examples of suitable heteroaryls include pyridyl,
pyrazinyl, furanyl, thienyl, pyrimidinyl, pyridone (including
N-substituted pyridones), isoxazolyl, isothiazolyl, oxazolyl,
thiazolyl, pyrazolyl, furazanyl, pyrrolyl, pyrazolyl, triazolyl,
1,2,4-thiadiazolyl, pyrazinyl, pyridazinyl, quinoxalinyl,
phthalazinyl, oxindolyl, imidazo[1,2-a]pyridinyl,
imidazo[2,1-b]thiazolyl, benzofurazanyl, indolyl, azaindolyl,
benzimidazolyl, benzothienyl, quinolinyl, imidazolyl,
thienopyridyl, quinazolinyl, thienopyrimidyl, pyrrolopyridyl,
imidazopyridyl, isoquinolinyl, benzoazaindolyl, 1,2,4-triazinyl,
benzothiazolyl and the like. The term "heteroaryl" also refers to
partially saturated heteroaryl moieties such as, for example,
tetrahydroisoquinolyl, tetrahydroquinolyl and the like.
[0967] "Aralkyl" or "arylalkyl" means an aryl-alkyl-group in which
the aryl and alkyl are as previously described. Preferred aralkyls
comprise a lower alkyl group. Non-limiting examples of suitable
aralkyl groups include benzyl, 2-phenethyl and naphthalenylmethyl.
The bond to the parent moiety is through the alkyl.
[0968] "Alkylaryl" means an alkyl-aryl-group in which the alkyl and
aryl are as previously described. Preferred alkylaryls comprise a
lower alkyl group. Non-limiting example of a suitable alkylaryl
group is tolyl. The bond to the parent moiety is through the
aryl.
[0969] "Cycloalkyl" means a non-aromatic mono- or multicyclic ring
system comprising about 3 to about 10 carbon atoms, preferably
about 5 to about 10 carbon atoms. Preferred cycloalkyl rings
contain about 5 to about 7 ring atoms. The cycloalkyl can be
optionally substituted with one or more "ring system substituents"
which may be the same or different, and are as defined above.
Non-limiting examples of suitable monocyclic cycloalkyls include
cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and the like.
Non-limiting examples of suitable multicyclic cycloalkyls include
1-decalinyl, norbornyl, adamantyl and the like.
[0970] "Cycloalkylalkyl" means a cycloalkyl moiety as defined above
linked via an alkyl moiety (defined above) to a parent core.
Non-limiting examples of suitable cycloalkylalkyls include
cyclohexylmethyl, adamantylmethyl and the like.
[0971] "Cycloalkenyl" means a non-aromatic mono or multicyclic ring
system comprising about 3 to about 10 carbon atoms, preferably
about 5 to about 10 carbon atoms which contains at least one
carbon-carbon double bond. Preferred cycloalkenyl rings contain
about 5 to about 7 ring atoms. The cycloalkenyl can be optionally
substituted with one or more "ring system substituents" which may
be the same or different, and are as defined above. Non-limiting
examples of suitable monocyclic cycloalkenyls include
cyclopentenyl, cyclohexenyl, cyclohepta-1,3-dienyl, and the like,
Non-limiting example of a suitable multicyclic cycloalkenyl is
norbornylenyl.
[0972] "Cycloalkenylalkyl" means a cycloalkenyl moiety as defined
above linked via an alkyl moiety (defined above) to a parent core.
Non-limiting examples of suitable cycloalkenylalkyls include
cyclopentenylmethyl, cyclohexenylmethyl and the like.
[0973] "Halogen" means fluorine, chlorine, bromine, or iodine.
Preferred are fluorine, chlorine and bromine. "Halo" refers to
fluoro, chloro, bromo or iodo.
[0974] "Ring system substituent" means a substituent attached to an
aromatic or non-aromatic ring system which, for example, replaces
an available hydrogen on the ring system. Ring system substituents
may be the same or different, each being independently selected
from the group consisting of alkyl, alkenyl, alkynyl, aryl,
heteroaryl, aralkyl, alkylaryl, heteroaralkyl, heteroarylalkenyl,
heteroarylalkynyl, alkylheteroaryl, hydroxy, hydroxyalkyl, alkoxy,
aryloxy, aralkoxy, acyl, aroyl, halo, nitro, cyano, carboxy,
alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkylsulfonyl,
arylsulfonyl, heteroarylsulfonyl, alkylthio, arylthio,
heteroarylthio, aralkylthio, heteroaralkylthio, cycloalkyl,
heterocyclyl, .dbd.O, .dbd.N--OY.sub.1, --O--C(O)-aryl,
--O--C(O)-cycloalkyl, --C(.dbd.N--CN)--NH.sub.2,
--C(.dbd.NH)--NH.sub.2, --C(.dbd.NH)--NH(alkyl), oxime (e.g.,
.dbd.N--OH), Y.sub.1Y.sub.2N--, Y.sub.1Y.sub.2N-alkyl-,
Y.sub.1Y.sub.2NC(O)--, Y.sub.1Y.sub.2NSO.sub.2-- and
--SO.sub.2NY.sub.1Y.sub.2, wherein Y.sub.1 and Y.sub.2 can be the
same or different and are independently selected from the group
consisting of hydrogen, alkyl, aryl, cycloalkyl, and aralkyl. "Ring
system substituent" may also mean a single moiety which
simultaneously replaces two available hydrogens on two adjacent
carbon atoms (one H on each carbon) on a ring system. Examples of
such moiety are methylene dioxy, ethylenedioxy,
--C(CH.sub.3).sub.2-- and the like which form moieties such as, for
example:
##STR00212##
[0975] "Heteroarylalkyl" means a heteroaryl moiety as defined above
linked via an alkyl moiety (defined above) to a parent core.
Non-limiting examples of suitable heteroaryls include
2-pyridinylmethyl, quinolinylmethyl and the like.
[0976] "Heterocyclyl" or "heterocycloalkyl" means a non-aromatic
saturated monocyclic or multicyclic ring system comprising about 3
to about 10 ring atoms, preferably about 5 to about 10 ring atoms,
in which one or more of the atoms in the ring system is an element
other than carbon, for example nitrogen, oxygen or sulfur, alone or
in combination. There are no adjacent oxygen and/or sulfur atoms
present in the ring system. Preferred heterocyclyls contain about 5
to about 6 ring atoms. The prefix aza, oxa or thia before the
heterocyclyl root name means that at least a nitrogen, oxygen or
sulfur atom respectively is present as a ring atom. Any --NH in a
heterocyclyl ring may exist protected such as, for example, as an
--N(Boc), --N(CBz), --N(Tos) group and the like; such protections
are also considered part of this invention. The heterocyclyl can be
optionally substituted by one or more "ring system substituents"
which may be the same or different, and are as defined herein. The
nitrogen or sulfur atom of the heterocyclyl can be optionally
oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide.
Non-limiting examples of suitable monocyclic heterocyclyl rings
include piperidyl, pyrrolidinyl, piperazinyl, morpholinyl,
thiomorpholinyl, thiazolidinyl, 1,4-dioxanyl, tetrahydrofuranyl,
tetrahydrothiophenyl, lactam, lactone, and the like. "Heterocyclyl"
also includes rings wherein .dbd.O replaces two available hydrogens
on the same carbon atom on a ring system (i.e., heterocyclyl
includes rings having a carbonyl in the ring). An example of such
moiety is pyrrolidone:
##STR00213##
[0977] "Heterocyclylalkyl" (or "heterocycloalkylalkyl") means a
heterocyclyl moiety as defined above finked via an alkyl moiety
(defined above) to a parent core. Non-limiting examples of suitable
heterocyclylalkyls include piperidinylmethyl, piperazinylmethyl and
the like.
[0978] "Heterocyclenyl" (or "heterocycloalkenyl") means a
non-aromatic monocyclic or multicyclic ring system comprising about
3 to about 10 ring atoms, preferably about 5 to about 10 ring
atoms, in which one or more of the atoms in the ring system is an
element other than carbon, for example nitrogen, oxygen or sulfur
atom, alone or in combination, and which contains at least one
carbon-carbon double bond or carbon-nitrogen double bond. There are
no adjacent oxygen and/or sulfur atoms present in the ring system.
Preferred heterocyclenyl rings contain about 5 to about 6 ring
atoms. The prefix aza, oxa or thia before the heterocyclenyl root
name means that at least a nitrogen, oxygen or sulfur atom
respectively is present as a ring atom. The heterocyclenyl can be
optionally substituted by one or more ring system substituents,
wherein "ring system substituent" is as defined above. The nitrogen
or sulfur atom of the heterocyclenyl can be optionally oxidized to
the corresponding N-oxide, S-oxide or S,S-dioxide. Non-limiting
examples of suitable heterocyclenyl groups include
1,2,3,4-tetrahydropyridinyl, 1,2-dihydropyridinyl,
1,4-dihydropyridinyl, 1,2,3,6-tetrahydropyridinyl,
1,4,5,6-tetrahydropyrimidinyl, 2-pyrrolinyl, 3-pyrrolinyl,
2-imidazolinyl, 2-pyrazolinyl, dihydroimidazolyl, dihydrooxazolyl,
dihydrooxadiazolyl, dihydrothiazolyl, 3,4-dihydro-2H-pyranyl,
dihydrofuranyl, fluorodihydrofuranyl, 7-oxabicyclo[2.2.1]heptenyl,
dihydrothiophenyl, dihydrothiopyranyl, and the like,
"Heterocyclenyl" also includes rings wherein .dbd.O replaces two
available hydrogens on the same carbon atom on a ring system (i.e.,
heterocyclyl includes rings having a carbonyl in the ring). An
example of such moiety is pyrrolidinone:
##STR00214##
[0979] "Heterocyclenylalkyl" (or "heterocycloalkenylalkyl") means a
heterocyclenyl moiety as defined above linked via an alkyl moiety
(defined above) to a parent core.
[0980] It should be noted that in hetero-atom containing ring
systems of this invention, there are no hydroxyl groups on carbon
atoms adjacent to a N, O or as well as there are no N or S groups
on carbon adjacent to another heteroatom. Thus, for example, in the
ring:
##STR00215##
there is no --OH attached directly to carbons marked 2 and 5.
[0981] It should also be noted that tautomeric forms such as, for
example, the moieties:
##STR00216##
are considered equivalent in certain embodiments of this
invention.
[0982] "Alkynylalkyl" means an alkynyl-alkyl-group in which the
alkynyl and alkyl are as previously described. Preferred
alkynylalkyls contain a lower alkynyl and a lower alkyl group. The
bond to the parent moiety is through the alkyl. Non-limiting
examples of suitable alkynylalkyl groups include
propargylmethyl.
[0983] "Heteroaralkyl" means a heteroaryl-alkyl-group in which the
heteroaryl and alkyl are as previously described. Preferred
heteroaralkyls contain a lower alkyl group. Non-limiting examples
of suitable aralkyl groups include pyridylmethyl, and
quinolin-3-ylmethyl. The bond to the parent moiety is through the
alkyl.
[0984] "Hydroxyalkyl" means a HO-alkyl-group in which alkyl is as
previously defined. Preferred hydroxyalkyls contain lower alkyl.
Non-limiting examples of suitable hydroxyalkyl groups include
hydroxymethyl and 2-hydroxyethyl.
[0985] "Acyl" means an H--C(O)--, alkyl-C(O)-- or
cycloalkyl-C(O)--, group in which the various groups are as
previously described. The bond to the parent moiety is through the
carbonyl. Preferred acyls contain a lower alkyl. Non-limiting
examples of suitable acyl groups include formyl, acetyl and
propanoyl.
[0986] "Aroyl" means an aryl-C(O)-- group in which the aryl group
is as previously described. The bond to the parent moiety is
through the carbonyl. Non-limiting examples of suitable groups
include benzoyl and 1-naphthoyl.
[0987] "Alkoxy" means an alkyl-O-- group in which the alkyl group
is as previously described. Non-limiting examples of suitable
alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy and
n-butoxy. The bond to the parent moiety is through the ether
oxygen.
[0988] "Aryloxy" means an aryl-O-- group in which the aryl group is
as previously described. Non-limiting examples of suitable aryloxy
groups include phenoxy and naphthoxy. The bond to the parent moiety
is through the ether oxygen.
[0989] "Aralkyloxy" means an aralkyl-O-- group in which the aralkyl
group is as previously described. Non-limiting examples of suitable
aralkyloxy groups include benzyloxy and 1- or 2-naphthalenemethoxy.
The bond to the parent moiety is through the ether oxygen.
[0990] "Alkylthio" means an alkyl-S-- group in which the alkyl
group is as previously described. Non-limiting examples of suitable
alkylthio groups include methylthio and ethylthio. The bond to the
parent moiety is through the sulfur.
[0991] "Arylthio" means an aryl-S-- group in which the aryl group
is as previously described. Non-limiting examples of suitable
arylthio groups include phenylthio and naphthylthio. The bond to
the parent moiety is through the sulfur.
[0992] "Aralkylthio" means an aralkyl-S-- group in which the
aralkyl group is as previously described. Non-limiting example of a
suitable aralkylthio group is benzylthio. The bond to the parent
moiety is through the sulfur.
[0993] "Alkoxycarbonyl" means an alkyl-O--CO-- group, Non-limiting
examples of suitable alkoxycarbonyl groups include methoxycarbonyl
and ethoxycarbonyl. The bond to the parent moiety is through the
carbonyl.
[0994] "Aryloxycarbonyl" means an aryl-O--C(O)-- group.
Non-limiting examples of suitable aryloxycarbonyl groups include
phenoxycarbonyl and naphthoxycarbonyl. The bond to the parent
moiety is through the carbonyl.
[0995] "Aralkoxycarbonyl" means an aralkyl-O--C(O)-- group.
Non-limiting example of a suitable aralkoxycarbonyl group is
benzyloxycarbonyl. The bond to the parent moiety is through the
carbonyl.
[0996] "Alkylsulfonyl" means an alkyl-S(O.sub.2)-- group. Preferred
groups are those in which the alkyl group is lower alkyl. The bond
to the parent moiety is through the sulfonyl.
[0997] "Arylsulfonyl" means an aryl-S(O.sub.2)-- group. The bond to
the parent moiety is through the sulfonyl.
[0998] The term "substituted" means that one or more hydrogens on
the designated atom is replaced with a selection from the indicated
group, provided that the designated atom's normal valency under the
existing circumstances is not exceeded, and that the substitution
results in a stable compound. Combinations of substituents and/or
variables are permissible only if such combinations result in
stable compounds. By "stable compound" or "stable structure" is
meant a compound that is sufficiently robust to survive isolation
to a useful degree of purity from a reaction mixture, and
formulation into an efficacious therapeutic agent.
[0999] The term "optionally substituted" means optional
substitution with the specified groups, radicals or moieties.
[1000] The term "purified", "in purified form" or "in isolated and
purified form" for a compound refers to the physical state of said
compound after being isolated from a synthetic process (e.g. from a
reaction mixture), or natural source or combination thereof. Thus,
the term "purified", "in purified form" or "in isolated and
purified form" for a compound refers to the physical state of said
compound after being obtained from a purification process or
processes described herein or well known to the skilled artisan
(e.g., chromatography, recrystallization and the like), in
sufficient purity to be characterizable by standard analytical
techniques described herein or well known to the skilled
artisan.
[1001] It should also be noted that any carbon as well as
heteroatom with unsatisfied valences in the text, schemes, examples
and Tables herein is assumed to have the sufficient number of
hydrogen atom(s) to satisfy the valences.
[1002] When a functional group in a compound is termed "protected",
this means that the group is in modified form to preclude undesired
side reactions at the protected site when the compound is subjected
to a reaction, Suitable protecting groups will be recognized by
those with ordinary skill in the art as well as by reference to
standard textbooks such as, for example, T. W. Greene et al,
Protective Groups in organic Synthesis (1991), Wiley, New York.
[1003] When any variable (e.g., aryl, heterocycle, R.sup.2, etc.)
occurs more than one time in any constituent or in Formula I, its
definition on each occurrence is independent of its definition at
every other occurrence.
[1004] As used herein, the term "composition" is intended to
encompass a product comprising the specified ingredients in the
specified amounts, as well as any product which results, directly
or indirectly, from combination of the specified ingredients in the
specified amounts.
[1005] Prodrugs and solvates of the compounds of the invention are
also contemplated herein. A discussion of prodrugs is provided in
T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems
(1987) 14 of the A.C.S. Symposium Series, and in Bioreversible
Carriers in Drug Design, (1987) Edward B. Roche, ed., American
Pharmaceutical Association and Pergamon Press. The term "prodrug"
means a compound (e.g., a drug precursor) that is transformed in
vivo to yield a compound of Formula (I) or a pharmaceutically
acceptable salt, hydrate or solvate of the compound. The
transformation may occur by various mechanisms (e.g., by metabolic
or chemical processes), such as, for example, through hydrolysis in
blood. A discussion of the use of prodrugs is provided by T.
Higuchi and W. Stella, "Pro-drugs as Novel Delivery Systems," Vol.
14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in
Drug Design, ed. Edward B. Roche, American Pharmaceutical
Association and Pergamon Press, 1987.
[1006] For example, if a compound of Formula (I) or a
pharmaceutically acceptable salt, hydrate or solvate of the
compound contains a carboxylic acid functional group, a prodrug can
comprise an ester formed by the replacement of the hydrogen atom of
the acid group with a group such as, for example,
(C.sub.1-C.sub.8)alkyl, (O.sub.2--C.sub.12)alkanoyloxymethyl,
1-(alkanoyloxy)ethyl having from 4 to 9 carbon atoms,
1-methyl-1-(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms,
alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms,
1-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms,
1-methyl-1-(alkoxycarbonyloxy)ethyl having from 5 to 8 carbon
atoms, N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon
atoms, 1-(N-(alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon
atoms, 3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl,
di-N,N--(C.sub.1-C.sub.2)alkylamino(C.sub.2-C.sub.3)alkyl (such as
.beta.-dimethylaminoethyl), carbamoyl-(C.sub.1-C.sub.2)alkyl,
N,N-di (C.sub.1-C.sub.2)alkylcarbamoyl-(C.sub.1-C.sub.2)alkyl and
piperidino-, pyrrolidino- or morpholino(C.sub.2-C.sub.3)alkyl, and
the like.
[1007] Similarly, if a compound of Formula (I) contains an alcohol
functional group, a prodrug can be formed by the replacement of the
hydrogen atom of the alcohol group with a group such as, for
example, (C.sub.1-C.sub.6)alkanoyloxymethyl,
1-((C.sub.1-C.sub.6)alkanoyloxy)ethyl,
1-methyl-1((C.sub.1-C.sub.6)alkanoyloxy)ethyl,
(C.sub.1-C.sub.6)alkoxycarbonyloxymethyl,
N--(C.sub.1-C.sub.5)alkoxycarbonylaminomethyl, succinoyl,
(C.sub.1-C.sub.6)alkanoyl, .alpha.-amino(C.sub.1-C.sub.4)alkanyl,
arylacyl and .alpha.-aminoacyl, or
.alpha.-aminoacyl-.alpha.-aminoacyl, where each .alpha.-aminoacyl
group is independently selected from the naturally occurring
L-amino acids, P(O)(OH).sub.2,
--P(O)(O(C.sub.1-C.sub.6)alkyl).sub.2 or glycosyl (the radical
resulting from the removal of a hydroxyl group of the hemiacetal
form of a carbohydrate), and the like.
[1008] If a compound of Formula (I) incorporates an amine
functional group, a prodrug can be formed by the replacement of a
hydrogen atom in the amine group with a group such as, for example,
R-carbonyl, RO-carbonyl, NRR'-carbonyl where R and R' are each
independently (C.sub.1-C.sub.10)alkyl, (C.sub.3-C.sub.7)
cycloalkyl, benzyl, or R-carbonyl is a natural .alpha.-aminoacyl or
natural .alpha.-aminoacyl, --C(OH)C(O)OY.sup.1 wherein Y.sup.1 is
H, (C.sub.1-C.sub.6)alkyl or benzyl, --C(OY.sup.2)Y.sup.3 wherein
Y.sup.2 is (C.sub.1-C.sub.4) alkyl and Y.sup.3 is
(C.sub.1-C.sub.6)alkyl, carboxy (C.sub.1-C.sub.6)alkyl,
amino(C.sub.1-C.sub.4)alkyl or mono-N-- or
di-N,N--(C.sub.1-C.sub.6)alkylaminoalkyl, --C(Y.sup.4)Y.sup.5
wherein Y.sup.4 is H or methyl and Y.sup.5 is mono-N-- or
di-N,N--(C.sub.1-C.sub.6)alkylamino morpholino, piperidin-1-yl or
pyrrolidin-1-yl, and the like.
[1009] One or more compounds of the invention may exist in
unsolvated as well as solvated forms with pharmaceutically
acceptable solvents such as water, ethanol, and the like, and it is
intended that the invention embrace both solvated and unsolvated
forms. "Solvate" means a physical association of a compound of this
invention with one or more solvent molecules. This physical
association involves varying degrees of ionic and covalent bonding,
including hydrogen bonding. In certain instances the solvate will
be capable of isolation, for example when one or more solvent
molecules are incorporated in the crystal lattice of the
crystalline solid. "Solvate" encompasses both solution-phase and
isolatable solvates. Non-limiting examples of suitable solvates
include ethanolates, methanolates, and the like. "Hydrate" is a
solvate wherein the solvent molecule is H.sub.2O.
[1010] One or more compounds of the invention may optionally be
converted to a solvate. Preparation of solvates is generally known.
Thus, for example, M. Caira at al, J. Pharmaceutical Sci., 93(3),
601-611 (2004) describe the preparation of the solvates of the
antifungal fluconazole in ethyl acetate as well as from water.
Similar preparations of solvates, hemisolvate, hydrates and the
like are described by E. C. van Tonder at al, AAPS PharmSciTech.,
5(1), article 12 (2004); and A. L. Bingham at al, Chem. Commun.,
603-604 (2001). A typical, non-limiting, process involves
dissolving the inventive compound in desired amounts of the desired
solvent (organic or water or mixtures thereof) at a higher than
ambient temperature, and cooling the solution at a rate sufficient
to form crystals which are then isolated by standard methods.
Analytical techniques such as, for example I. R. spectroscopy, show
the presence of the solvent (or water) in the crystals as a solvate
(or hydrate).
[1011] "Effective amount" or "therapeutically effective amount" is
meant to describe an amount of compound or a composition of the
present invention effective in inhibiting the above-noted diseases
and thus producing the desired therapeutic, ameliorative,
inhibitory or preventative effect.
[1012] The compounds of Formula (I) can form salts which are also
within the scope of this invention. Reference to a compound of
Formula (I) herein is understood to include reference to salts
thereof, unless otherwise indicated. The term "salt(s)", as
employed herein, denotes acidic salts formed with inorganic and/or
organic acids, as well as basic salts formed with inorganic and/or
organic bases. In addition, when a compound of Formula I contains
both a basic moiety, such as, but not limited to a pyridine or
imidazole, and an acidic moiety, such as, but not limited to a
carboxylic acid, zwitterions ("inner salts") may be formed and are
included within the term "salt(s)" as used herein. Pharmaceutically
acceptable (i.e., non-toxic, physiologically acceptable) salts are
preferred, although other salts are also useful. Salts of the
compounds of the Formula (I) may be formed, for example, by
reacting a compound of Formula (I) with an amount of acid or base,
such as an equivalent amount, in a medium such as one in which the
salt precipitates or in an aqueous medium followed by
lyophilization.
[1013] Exemplary acid addition salts include acetates, ascorbates,
benzoates, benzenesulfonates, bisulfates, borates, butyrates,
citrates, camphorates, camphorsulfonates, fumarates,
hydrochlorides, hydrobromides, hydroiodides, lactates, maleates,
methanesulfonates, naphthalenesulfonates, nitrates, oxalates,
phosphates, propionates, salicylates, succinates, sulfates,
tartarates, thiocyanates, toluenesulfonates (also known as
tosylates,) and the like. Additionally, acids which are generally
considered suitable for the formation of pharmaceutically useful
salts from basic pharmaceutical compounds are discussed, for
example, by P. Stahl et al, Camille G. (eds.) Handbook of
Pharmaceutical Salts. Properties, Selection and Use. (2002) Zurich:
Wiley-VCH; S. Berge et al, Journal of Pharmaceutical Sciences
(1977) 66(1) 1-19; P. Gould, International J. of Pharmaceutics
(1986) 33 201-217; Anderson et al, The Practice of Medicinal
Chemistry (1996), Academic Press, New York; and in The Orange Book
(Food & Drug Administration, Washington, D.C. on their
website). These disclosures are incorporated herein by reference
thereto.
[1014] Exemplary basic salts include ammonium salts, alkali metal
salts such as sodium, lithium, and potassium salts, alkaline earth
metal salts such as calcium and magnesium salts, salts with organic
bases (for example, organic amines) such as dicyclohexylamines,
t-butyl amines, and salts with amino acids such as arginine, lysine
and the like. Basic nitrogen-containing groups may be quarternized
with agents such as lower alkyl halides (e.g. methyl, ethyl, and
butyl chlorides, bromides and iodides), dialkyl sulfates (e.g.
dimethyl, diethyl, and dibutyl sulfates), long chain halides (e.g.
decyl, lauryl, and stearyl chlorides, bromides and iodides),
aralkyl halides (e.g. benzyl and phenethyl bromides), and
others.
[1015] All such acid salts and base salts are intended to be
pharmaceutically acceptable salts within the scope of the invention
and all acid and base salts are considered equivalent to the free
forms of the corresponding compounds for purposes of the
invention.
[1016] Pharmaceutically acceptable esters of the present compounds
include the following groups: (1) carboxylic acid esters obtained
by esterification of the hydroxy groups, in which the non-carbonyl
moiety of the carboxylic acid portion of the ester grouping is
selected from straight or branched chain alkyl (for example,
acetyl, n-propyl, t-butyl, or n-butyl), alkoxyalkyl (for example,
methoxymethyl), aralkyl (for example, benzyl), aryloxyalkyl (for
example, phenoxymethyl), aryl (for example, phenyl optionally
substituted with, for example, halogen, C.sub.1-4alkyl, or
C.sub.1-4alkoxy or amino); (2) sulfonate esters, such as alkyl- or
aralkylsulfonyl (for example, methanesulfonyl); (3) amino acid
esters (for example, L-valyl or L-isoleucyl); (4) phosphonate
esters and (5) mono-, di- or triphosphate esters. The phosphate
esters may be further esterified by, for example, a C.sub.1-20
alcohol or reactive derivative thereof, or by a 2,3-di
(C.sub.6-24)acyl glycerol.
[1017] Compounds of formula (I), and salts, solvates, esters and
prodrugs thereof, may exist in their tautomeric form (for example,
as an amide, enol, keto or imino ether). All such tautomeric forms
are contemplated herein as part of the present invention.
[1018] The compounds of formula (I) may contain asymmetric or
chiral centers, and, therefore, exist in different stereoisomeric
forms. It is intended that all stereoisomeric forms of the
compounds of formula (I) as well as mixtures thereof, including
racemic mixtures, form part of the present invention. In addition,
the present invention embraces all geometric and positional
isomers. For example, if a compound of formula (I) incorporates a
double bond or a fused ring, both the cis- and trans-forms, as well
as mixtures, are embraced within the scope of the invention.
[1019] Diastereomeric mixtures can be separated into their
individual diastereomers on the basis of their physical chemical
differences by methods well known to those skilled in the art, such
as, for example, by chromatography and/or fractional
crystallization. Enantiomers can be separated by converting the
enantiomeric mixture into a diastereomeric mixture by reaction with
an appropriate optically active compound (e.g., chiral auxiliary
such as a chiral alcohol or Mosher's acid chloride), separating the
diastereomers and converting (e.g., hydrolyzing) the individual
diastereomers to the corresponding pure enantiomers. Also, some of
the compounds of formula (I) may be atropisomers (e.g., substituted
biaryls) and are considered as part of this invention. Enantiomers
can also be separated by use of chiral HPLC column.
[1020] It is also possible that the compounds of formula (I) may
exist in different tautomeric forms, and all such forms are
embraced within the scope of the invention. Also, for example, all
keto-enol and imine-enamine forms of the compounds are included in
the invention.
[1021] All stereoisomers (for example, geometric isomers, optical
isomers and the like) of the present compounds (including those of
the salts, solvates, esters and prodrugs of the compounds as well
as the salts, solvates and esters of the prodrugs), such as those
which may exist due to asymmetric carbons on various substituents,
including enantiomeric forms (which may exist even in the absence
of asymmetric carbons), rotameric forms, atropisomers, and
diastereomeric forms, are contemplated within the scope of this
invention, as are positional isomers (such as, for example,
4-pyridyl and 3-pyridyl), (For example, if a compound of formula
(I) incorporates a double bond or a fused ring, both the cis- and
trans-forms, as well as mixtures, are embraced within the scope of
the invention. Also, for example, all keto-enol and imine-enamine
forms of the compounds are included in the invention.) Individual
stereoisomers of the compounds of the invention may, for example,
be substantially free of other isomers, or may be admixed, for
example, as racemates or with all other, or other selected,
stereoisomers. The chiral centers of the present invention can have
the S or R configuration as defined by the IUPAC 1974
Recommendations. The use of the terms "salt", "solvate", "ester",
"prodrug" and the like, is intended to equally apply to the salt,
solvate, ester and prodrug of enantiomers, stereoisomers, rotamers,
tautomers, positional isomers, racemates or prodrugs of the
inventive compounds.
[1022] The present invention also embraces isotopically-labelled
compounds of the present invention which are identical to those
recited herein, but for the fact that one or more atoms are
replaced by an atom having an atomic mass or mass number different
from the atomic mass or mass number usually found in nature.
Examples of isotopes that can be incorporated into compounds of the
invention include isotopes of hydrogen, carbon, nitrogen, oxygen,
phosphorus, fluorine and chlorine, such as .sup.2H, .sup.3H,
.sup.13C, .sup.14C, .sup.15N, .sup.18O, .sup.17O, .sup.31P,
.sup.32P, .sup.35S, .sup.18F, and .sup.36Cl, respectively.
[1023] Certain isotopically-labelled compounds of formula (I)
(e.g., those labeled with .sup.3H and .sup.14C) are useful in
compound and/or substrate tissue distribution assays. Tritiated
(i.e., .sup.3H) and carbon-14 (i.e., .sup.14C) isotopes are
particularly preferred for their ease of preparation and
detectability. Further, substitution with heavier isotopes such as
deuterium (i.e., .sup.2H) may afford certain therapeutic advantages
resulting from greater metabolic stability (e.g., increased in vivo
half-life or reduced dosage requirements) and hence may be
preferred in some circumstances. Isotopically labelled compounds of
formula (I) can generally be prepared by following procedures
analogous to those disclosed in the Schemes and/or in the Examples
hereinbelow, by substituting an appropriate isotopically labelled
reagent for a non-isotopically labelled reagent.
[1024] Polymorphic forms of the compounds of formula (I), and of
the salts, solvates, esters and prodrugs of the compounds of
formula (I), are intended to be included in the present
invention.
[1025] The compounds according to the invention can have
pharmacological properties; in particular, the compounds of formula
(I) can be modulators of gamma secretase (including inhibitors,
antagonists and the like).
[1026] More specifically, the compounds of formula (I) can be
useful in the treatment of a variety of disorders of the central
nervous system including, for example, including, but not limited
to, Alzheimer's disease, AIDS-related dementia, Parkinson's
disease, amyotrophic lateral sclerosis, retinitis pigmentosa,
spinal muscular atrophy and cerebellar degeneration and the
like.
[1027] Another aspect of this invention is a method of treating a
mammal (e.g., human) having a disease or condition of the central
nervous system by administering a therapeutically effective amount
of at least one compound of formula (I), or a pharmaceutically
acceptable salt, solvate, ester or prodrug of said compound to the
mammal.
[1028] A preferred dosage is about 0.001 to 500 mg/kg of body
weight/day of the compound of formula (I). An especially preferred
dosage is about 0.01 to 25 mg/kg of body weight/day of a compound
of formula (I), or a pharmaceutically acceptable salt or solvate of
said compound.
[1029] The compounds of this invention may also be useful in
combination (administered together or sequentially) with one or
more additional agents listed above.
[1030] The compounds of this invention may also be useful in
combination (administered together or sequentially) with one or
more compounds selected from the group consisting of A.beta.
antibody inhibitors, gamma secretase inhibitors and beta secretase
inhibitors.
[1031] If formulated as a fixed dose, such combination products
employ the compounds of this invention within the dosage range
described herein and the other pharmaceutically active agent or
treatment within its dosage range.
[1032] Accordingly, in an aspect, this invention includes
combinations comprising an amount of at least one compound of
formula (I), or a pharmaceutically acceptable salt, solvate, ester
or prodrug thereof, and an amount of one or more additional agents
listed above wherein the amounts of the compounds/treatments result
in desired therapeutic effect.
[1033] The pharmacological properties of the compounds of this
invention may be confirmed by a number of pharmacological assays.
Certain assays are exemplified later in this document.
[1034] This invention is also directed to pharmaceutical
compositions which comprise at least one compound of formula (I),
or a pharmaceutically acceptable salt, solvate, ester or prodrug of
said compound and at least one pharmaceutically acceptable
carrier.
[1035] For preparing pharmaceutical compositions from the compounds
described by this invention, inert, pharmaceutically acceptable
carriers can be either solid or liquid. Solid form preparations
include powders, tablets, dispersible granules, capsules, cachets
and suppositories. The powders and tablets may be comprised of from
about 5 to about 95 percent active ingredient. Suitable solid
carriers are known in the art, e.g., magnesium carbonate, magnesium
stearate, talc, sugar or lactose, Tablets, powders, cachets and
capsules can be used as solid dosage forms suitable for oral
administration. Examples of pharmaceutically acceptable carriers
and methods of manufacture for various compositions may be found in
A. Gennaro (ed.), Remington's Pharmaceutical Sciences, 18.sup.th
Edition, (1990), Mack Publishing Co., Easton, Pa.
[1036] Liquid form preparations include solutions, suspensions and
emulsions. As an example may be mentioned water or water-propylene
glycol solutions for parenteral injection or addition of sweeteners
and opacifiers for oral solutions, suspensions and emulsions.
Liquid form preparations may also include solutions for intranasal
administration.
[1037] Aerosol preparations suitable for inhalation may include
solutions and solids in powder form, which may be in combination
with a pharmaceutically acceptable carrier, such as an inert
compressed gas, e.g. nitrogen.
[1038] Also included are solid form preparations that are intended
to be converted, shortly before use, to liquid form preparations
for either oral or parenteral administration. Such liquid forms
include solutions, suspensions and emulsions.
[1039] The compounds of the invention may also be deliverable
transdermally. The transdermal compositions can take the form of
creams, lotions, aerosols and/or emulsions and can be included in a
transdermal patch of the matrix or reservoir type as are
conventional in the art for this purpose.
[1040] The compounds of this invention may also be delivered
subcutaneously.
[1041] Preferably the compound is administered orally.
[1042] Preferably, the pharmaceutical preparation is in a unit
dosage form. In such form, the preparation is subdivided into
suitably sized unit doses containing appropriate quantities of the
active component, e.g., an effective amount to achieve the desired
purpose.
[1043] The quantity of active compound in a unit dose of
preparation may be varied or adjusted from about 1 mg to about 100
mg, preferably from about 1 mg to about 50 mg, more preferably from
about 1 mg to about 25 mg, according to the particular
application.
[1044] The actual dosage employed may be varied depending upon the
requirements of the patient and the severity of the condition being
treated. Determination of the proper dosage regimen for a
particular situation is within the skill of the art. For
convenience, the total daily dosage may be divided and administered
in portions during the day as required.
[1045] The amount and frequency of administration of the compounds
of the invention and/or the pharmaceutically acceptable salts
thereof will be regulated according to the judgment of the
attending clinician considering such factors as age, condition and
size of the patient as well as severity of the symptoms being
treated. A typical recommended daily dosage regimen for oral
administration can range from about 1 mg/day to about 500 mg/day,
preferably 1 mg/day to 200 mg/day, in two to four divided
doses.
[1046] Another aspect of this invention is a kit comprising a
therapeutically effective amount of at least one compound of
formula (I), or a pharmaceutically acceptable salt, solvate, ester
or prodrug of said compound and a pharmaceutically acceptable
carrier, vehicle or diluent.
[1047] Yet another aspect of this invention is a kit comprising an
amount of at least one compound of formula (I), or a
pharmaceutically acceptable salt, solvate, ester or prodrug of said
compound and an amount of at least one additional agent listed
above, wherein the amounts of the two or more ingredients result in
desired therapeutic effect.
[1048] The invention disclosed herein is exemplified by the
following illustrative schemes and examples which should not be
construed to limit the scope of the disclosure. Alternative
mechanistic pathways and analogous structures will be apparent to
those skilled in the art.
[1049] The compounds of the invention can be prepared by the
schemes and examples below. Compounds of the invention wherein
G.sup.5 moiety is bound to G.sup.3 (i.e., position (2)) can be
prepared by the same chemistry unless indicated otherwise.
##STR00217## ##STR00218## ##STR00219## ##STR00220## ##STR00221##
##STR00222## ##STR00223## ##STR00224## ##STR00225##
Example 1
##STR00226##
[1050] Step A:
##STR00227##
[1052] To a round bottom flask at room temperature. containing
formic acid (85%, 27 mL, 624.4 mmol) was added acetic anhydride (16
mL, 169.5 mmol) dropwise. The reaction stirred for 45 min. followed
by the dropwise addition of a solution of 4-bromo-2-methoxyaniline
(9.01 g, 44.6 mmol) in THF (56 mL). The reaction mixture was
quenched with ice-water after 23 h and the resulting precipitate
was filtered to afford compound 100.1 (9.20 g, 90%) as a brown
solid.
Step B:
##STR00228##
[1054] To a round bottom flask at room temperature containing a
mixture of compound 100.1 (9.20 g, 39.9 mmol), cesium carbonate
(26.05 g, 79.9 mmol), and potassium iodide (0.66 g, 3.9 mmol) in
DMF (40 mL) was added chloroacetone (6.7 mL, 79.9 mmol) dropwise.
The reaction stirred for 3 h followed by addition of cesium
carbonate (13.02 g, 39.9 mmol) and chloroacetone (3.35 mL, 39.9
mmol). After 19 h the reaction was diluted with water, extracted
with 75% ethyl acetate/hexanes, washed with brine, dried over
Na.sub.2SO.sub.4, and concentrated in vacuo. The crude material was
purified by silica gel chromatography with ethyl
acetate/dichloromethane to afford compound 100.2 (10.94 g, 96%) as
a beige solid.
Step C:
##STR00229##
[1056] A round bottom flask at room temperature containing a
mixture of compound 100.2 (10.94 g, 38.24 mmol), ammonium acetate
(14.74 g, 191.2 mmol), and acetic acid (22 mL, 382.4 mmol) was
heated to 140.degree. C. The reaction stirred for 1 h and then was
poured over ice-water. Ammonium hydroxide (60 mL) was added to the
mixture, extracted with ethyl acetate, dried over Na.sub.2SO.sub.4,
and concentrated in vacuum. The crude material was purified by
silica gel chromatography with acetone/ammonium
hydroxide/dichloromethane to afford compound 100.3 (7.57 g, 74%) as
a brown/orange solid.
Step D:
##STR00230##
[1058] To compound 100.3 (1.4 mmol), Bu.sub.3SnSnBu.sub.3 (2.1
mmol) and Potassium carbonate (7 mmol) was added 30 ml Toluene
followed by Pd(PPh.sub.3).sub.4 (0.14 mmol) then heat to
120.degree. C. for 2 hrs. The reaction was worked up by cooling to
room temperature then adding water and dichloromethane. Extract
aqueous layer 3.times. dichloromethane, then dry over sodium
sulfate and filter and concentrate to dryess. The residue was
purified by chromatography over silica gel (eluted with
dichloromethane/MeOH 99:1 to 90:10) to provide product 100.4.
Step E:
##STR00231##
[1060] To compound 100.5 (1.0 mmol), alpha-methyl 3.5
difluorobenzyl bromide (1.5 mmol) and Potassium carbonate (5.0
mmol) will be added 30 mL. DMF. The mixture will be stirred at room
temperature overnight. The reaction will be worked up by adding
water and EtOAc. Extract aqueous layer 3.times.EtOAc, then dry over
sodium sulfate and filter and concentrate to dryess. The residue
will be purified by chromatography over silica gel to provide
product 100.6.
Step F:
##STR00232##
[1062] To compound 100.6 (1.0 mmol) in DMF (6.0 mL) will be added
N-bromosuccinimide (1.1 mmol) at room temperature. The mixture will
be stirred at room temperature overnight. The reaction will be
worked up by adding aqueous Na.sub.2S.sub.2O.sub.3 and EtOAc.
Extract aqueous layer 3.times.EtOAc, then dry over sodium sulfate
and filter and concentrate to dryess. The residue will be purified
by chromatography over silica gel to provide product 100.7.
Step G:
##STR00233##
[1064] To compound 100.7 (1.4 mmol), 100.4 (2.1 mmol) and Potassium
carbonate (7 mmol) will be added 30 mL Toluene followed by
Pd(PPh.sub.3).sub.4 (0.14 mmol) then heat to 120.degree. C. for 2
hrs. The reaction will be worked up by cooling to RT then adding
water and dichloromethane. Extract aqueous layer 3.times.
dichloromethane, then dry over sodium sulfate and filter and
concentrate to dryess. The residue will be purified by
chromatography over silica gel to provide product 100.
[1065] Compounds 101 to 124 will be prepared following a procedure
similar to the preparation of compound 100.
##STR00234## ##STR00235## ##STR00236## ##STR00237##
Assay:
[1066] Secretase Reaction and A.beta. Analysis in Whole Cells:
HEK293 cells overexpressing APP with Swedish and London mutations
is treated with the specified compounds for 5 hour at 37.degree. C.
in 100 ml of DMEM medium containing 10% fetal bovine serum. At the
end of the incubation, total A.beta., A.beta.40 and A.beta.42 is
measured using electrochemiluminescence (ECL) based sandwich
immunoassays. Total A.beta. is determined using a pair of
antibodies TAG-W02 and biotin-4G8, A.beta.40 is identified with
antibody pairs TAG-G2-10 and biotin-4G8, while A.beta.42 is
identified with TAG-G2-11 and biotin-4G8. The ECL signal is
measured using Sector Imager 2400 (Meso Scale Discovery).
[1067] MS Analysis of A.beta. Profile: A.beta. profile in
conditioned media is determined using surface enhanced laser
desorption/ionization (SELDI) mass spectrometry. Conditioned media
is incubated with antibody W02 coated PS20 ProteinChip array. Mass
spectra of A.beta. captured on the array is read on SELDI
ProteinChip Reader (Bio-Rad) according to manufacturer's
instructions.
[1068] CSF A.beta. Analysis: A.beta. in rat CSF is determined using
MSD technology as described above. A.beta.40 is measured using
antibody pair Tag-G2-10 and biotin-4G8, while A.beta.42 is measured
using Tag-anti A.beta.42 (Meso Scale Discovery) and biotin-4G8. The
ECL signal is measured using Sector Imager 2400 (Meso Scale
Discovery).
[1069] Matrix-assisted laser desorption/ionization mass
spectrometric (MALDI MS) analysis of A.beta. is performed on a
Voyager-DE STR mass spectrometer (ABI, Framingham, Mass.). The
instrument is equipped with a pulsed nitrogen laser (337 nm). Mass
spectra is acquired in the linear mode with an acceleration voltage
of 20 kV. Each spectrum presented in this work represents an
average of 256 laser shots. To prepare the sample-matrix solution,
1 .mu.L of immunoprecipitated A.beta. sample is mixed with 3 .mu.L
of saturated .alpha.-cyano-4-hydroxycinnamic acid solution in 0.1%
TFA/acetonitrile. The sample-matrix solution is then applied to the
sample plate and dried at ambient temperature prior to mass
spectrometric analysis. All the spectra are externally calibrated
with a mixture of bovine insulin and ACTH (18-39 clip).
[1070] While the present invention has been described in
conjunction with the specific embodiments set forth above, many
alternatives, modifications and other variations thereof will be
apparent to those of ordinary skill in the art. All such
alternatives, modifications and variations are intended to fall
within the spirit and scope of the present invention.
* * * * *